Crystal comprising (2r)-2-propyloctanoic acid and amine

ABSTRACT

According to the present invention, crystals comprising (2R)-2-propyloctanoic acid and an amine, which can be used as bulk drugs for safely orally administrable solid preparations with keeping the pharmacological effect, are provided. Among these crystals, the crystal with dibenzylamine per se is particularly useful as bulk drug for pharmaceuticals and can be used as an intermediate to produce (2R)-2-propyloctanoic acid having an optical purity of more than 99.5% e.e. which has not been obtained.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.11/579,071 filed Oct. 27, 2006, which is a 371 of PCT/JP05/008462 filedApr. 27, 2005, which claims priority to JP 2004-134655 filed Apr. 28,2004. The entire disclosures of the prior applications are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to crystals comprising(2R)-2-propyloctanoic acid and amines useful as bulk drugs forpharmaceuticals.

BACKGROUND ART

Orally administrable pharmaceuticals are mainly prescribed as oral solidpharmaceutical preparations such as tablets, powders, capsules, and thelike. Among these preparations, tablets have been most often used athome and abroad because they can easily be administered and handled.

On the other hand, (2R)-2-propyloctanoic acid has been known to be auseful compound in a variety of diseases including cerebral apoplexysince it acts to improve the function of astrocytes (EP Patent 0632008and EP-A-1174131). However, it was hard to formulate(2R)-2-propyloctanoic acid into such a formulation as tablets and toadminister it to patients, because it is oil.

In general, it is considered preferable that the bulk drugs forpharmaceuticals, particularly the materials used as the bulk drugs forpharmaceuticals for oral solid preparations, are those obtained ascrystals since the crystals allow a stable supply in large quantitiesand relatively easy formulation into such a form as tablets.

Accordingly, the materials which are intended to use as oral solidpreparations are tried to crystallize by performing such an operation asformation of salts, when they are amorphous or liquid materials in afree state.

The above Patent Documents describe that (2R)-2-propyloctanoic acid maybe formed into salts including salts with alkali metals (potassium,sodium, etc.), salts with alkaline earth metals (e.g., calcium,magnesium, etc.), ammonium salt, salts with organic amines (e.g.,tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucan, etc.), and the like.

The sodium salt of (2R)-2-propyloctanoic acid, i.e., alkali metal salt,however, was obtained not as crystals but as waxy solid in practicalpreparation; this was difficult to handle and had no desiredphysicochemical properties adaptable as a bulk drug for pharmaceuticalsdirected to oral solid preparations.

On the other hand, it is known that as for (2R)-2-propyloctanoic acidamine salts, a salt of (2R)-2-propyloctanoic acid with(R)-(+)-1-phenylethylamine can be obtained as a salt, which is used asan intermediate in production of optically highly pure(2R)-2-propyloctanoic acid (see: WO03/051852). The salts with otheramines, however, have not yet been synthesized practically up to date;therefore, it was unclear whether it can be obtained as crystals and isendurable in use as a bulk drug for pharmaceuticals in oral solidpreparations.

DISCLOSURE OF INVENTION

The problem to be solved by the present invention, accordingly, is toprovide a crystal comprising (2R)-2-propyloctanoic acid and an amine,which can be used safely, for example, as a bulk drug for oral solidpharmaceutical preparations with keeping the pharmacological activity of(2R)-2-propyloctanoic acid.

In general, whether a compound formed by an acid and a base can becrystallized or not, depends on the combination of an acid and base, andfurther on the solvent used in crystallization. In other words,successful crystallization does not depend on the property of an acid orbase itself. Therefore, even if combination of a certain acid and acertain base gives crystals successfully, the acid does not necessarilygive crystals in combination with any kind of base.

The present inventors tried assiduously to obtain crystals comprising(2R)-2-propyloctanoic acid and an amine using a variety of amines and avariety of solvents. As a result, they succeeded in obtaining somecrystals from a large number of combinations, which crystals can be usedas bulk drugs for oral solid pharmaceutical preparations. Thus, thepresent invention was completed.

In addition, the present inventors found that among the resultingcrystals a crystal comprising (2R)-2-propyloctanoic acid anddibenzylamine is also useful as an intermediate to obtain very highlyoptically pure (2R)-2-propyloctanoic acid.

That is, the present invention relates to the followings:

1. An isolated crystal comprising (2R)-2-propyloctanoic acid and amine,excluding (R)-(+)-1-phenylethylamine;2. The crystal according to the above 1, wherein the amine is(+)-dehydroabietylamine, (R)-(−)-2-phenylglycinol,(S)-(+)-2-phenylglycinol, (−)-cis-myrtanylamine,(R)-(+)-1-(p-tolyl)ethylamine, (R)-(+)-1-(1-naphthyl)ethylamine,(S)-(−)-1-(1-naphthyl)ethylamine, L-tyrosinamide,(1S,2R)-(+)-2-amino-1,2-diphenylethanol,(1R,2S)-(−)-2-amino-1,2-diphenylethanol,(+)-cis-2-benzylaminocyclohexanemethanol,(−)-cis-2-benzylaminocyclohexanemethanol,(S)-(−)-2-amino-3-phenyl-1-propanol,(R)-(+)-2-amino-3-phenyl-1-propanol, (R-(+)-1-(4-bromophenyl)ethylamine,(R)-(+)-1-phenylpropylamine, dibenzylamine, 1,2-diphenylethylamine,benzhydrylamine, cyclohexylamine, dicyclohexylamine, cycloheptylamine,N-ethylcyclohexylamine, 2,2,6,6-tetramethyl-4-piperidinol,2-(2-methoxyphenyl)ethylamine, dimethoxyphenyl)ethylamine,N-isopropylbenzylamine, or N-butylbenzylamine;3. A pharmaceutical composition, comprising the crystal according to theabove 2 as an active ingredient;4. The pharmaceutical composition according to the above 3, which is anagent for prevention, treatment and/or suppression of symptomprogression symptom progression for neurodegenerative diseases,neuropathies or diseases in need of nerve regeneration;5. A pharmaceutical composition, comprising the crystal according to theabove 2 in combination with at least one selected from ananticonvulsant, an acetylcholinesterase inhibitor, a neurotrophicfactor, an aldose reductase inhibitor, an antithrombotic, an oralanticoagulant, a synthetic antithrombin drug, an antiplatelet drug, athrombolytic agent, a Factor Xa inhibitor, a Factor VIIa inhibitor, acerebral blood flow and metabolism improver, an antioxidant, a glycerinpreparation, a β-secretase inhibitor, a β-amyloid protein aggregationinhibitor, a cerebral function activator, a dopamine receptor agonist, amonoamine oxidase inhibitor, an anticholinergic drug, a COMT inhibitor,a therapeutic agent for amyotrophic lateral sclerosis, a therapeuticagent for hyperlipidemia, an apoptosis inhibitor, a nervedifferentiation and regeneration promoter, a non-steroidalanti-inflammatory drug, a steroid drug, and a sexual hormone or itsderivative;6. A method for prevention, treatment and/or suppression of symptomprogression symptom progression for neurodegenerative diseases,neuropathies or diseases in need of nerve regeneration, which comprisesadministering to a mammal an effective amount of the crystal accordingto the above 2;7. Use of the crystal according to the above 2 for the manufacture of anagent for prevention, treatment and/or suppression of symptomprogression symptom progression for neurodegenerative diseases,neuropathies or diseases in need of nerve regeneration;8. An isolated crystal comprising 2-propyloctanoic acid anddibenzylamine;9. The isolated crystal according to the above 2, wherein the2-propyloctanoic acid is (2R)-2-propyloctanoic acid;10. The isolated crystal according to the above 9, which has an opticalpurity of 97% e.e. or more;11. The isolated crystal according to the above 9, which has a specificrotation of −3.6°;12. A process for producing (2R)-2-propyloctanoic acid having an opticalpurity of 97% e.e. or more, which comprises:

dissolving (2R)-2-propyloctanoic acid having an optical purity of 70%e.e. or more and an optically inactive amine in a solvent to give asolution;

repeating the following steps (1)-(3) 0 to 3 times

(1) preferentially crystallizing a crystal comprising the(2R)-2-propyloctanoic acid with the optically inactive amine from thesolution;(2) separating and collecting the precipitated crystal;(3) dissolving the crystal in a solvent to give a solution;

preferentially crystallizing a crystal comprising the(2R)-2-propyloctanoic acid with the optically inactive amine from thesolution; and

separating and collecting the precipitated crystal to give a free(2R)-2-propyloctanoic acid;

13. The process according to the above 12, wherein the opticallyinactive amine is dibenzylamine;14. (2R)-2-propyloctanoic acid having an optical purity of more than99.5% e.e.;15. The (2R)-2-propyloctanoic acid according to the above 14, which isobtainable by the process according to the above 13;16. A pharmaceutical composition, comprising (2R)-2-propyloctanoic acidaccording to the above 14;17. The pharmaceutical composition according to the above 16, which isan agent for prevention, treatment and/or suppression of symptomprogression for neurodegenerative diseases, neuropathies or diseases inneed of nerve regeneration;18. The isolated crystal according to the above 9, which has a meltingpoint of about 79.0 to about 80.2° C.;19. The isolated crystal according to the above 9, which has diffractionangles (20) of 15.27, 17.03, 19.04, 19.99, 21.36, 22.91, 24.21, 26.09,26.70, 28.42, 30.83, 34.06 in powdered X-ray diffraction spectrum;20. The isolated crystal according to the above 9, wherein the powderedX-ray diffraction spectrum is powdered X-ray diffraction spectrum shownin FIG. 1;21. The isolated crystal according to the above 9, which has absorptionsat 3434, 3068, 3036, 2957, 2926, 2872, 2853, 2756, 2621, 2454, 1948,1638, 1498, 1466, 1457, 1415, 1379, 1342, 1321, 1212, 1141, 1112, 1096,1044, 989, 936, 905, 812, 763, 744, 694 cm⁻¹ in infrared absorptionspectrum;22. The isolated crystal according to the above 9, wherein the infraredabsorption spectrum is infrared absorption spectrum shown in FIG. 2;23. A production process of the crystal according to the above 1;24. A method for improving the optical purity of (2R)-2-propyloctanoicacid, which comprises using dibenzylamine;

and the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a chart of powdered X-ray diffraction spectrum of a crystalcomprising (2R)-2-propyloctanoic acid and dibenzylamine.

FIG. 2 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and dibenzylamine.

FIG. 3 shows a chart of differential scanning calorimetry (DSC) of acrystal comprising (2R)-2-propyloctanoic acid and dibenzylamine.

FIG. 4 shows a chart of powdered X-ray diffraction spectrum of a crystalcomprising (2R)-2-propyloctanoic acid and (+)-dehydroabietylamine.

FIG. 5 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-2-propyloctanoic acid and (+)-dehydroabietylamine.

FIG. 6 shows a chart of powdered X-ray diffraction spectrum of a crystalcomprising (2R)-2-propyloctanoic acid and (R)-(−)-2-phenylglycinol.

FIG. 7 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and (R)-(−)-2-phenylglycinol.

FIG. 8 shows a chart of powdered X-ray diffraction spectrum of a crystalcomprising (2R)-2-propyloctanoic acid and (S)-(+)-2-phenylglycinol.

FIG. 9 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and (S)-(+)-2-phenylglycinol.

FIG. 10 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and (−)-cis-myrtanylamine.

FIG. 11 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and (−)-cis-myrtanylamine.

FIG. 12 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(p-tolyl)ethylamine.

FIG. 13 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and (R)-(+)-1-(p-tolyl)ethylamine.

FIG. 14 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(1-naphthyl)ethylamine.

FIG. 15 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(1-naphthyl)ethylamine.

FIG. 16 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(S)-(−)-1-(1-naphthyl)ethylamine.

FIG. 17 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(S)-(−)-1-(1-naphthyl)ethylamine.

FIG. 18 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and L-tyrosinamide.

FIG. 19 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and L-tyrosinamide.

FIG. 20 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(1S,2R)-(+)-2-amino-1,2-diphenylethanol.

FIG. 21 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(1S,2R)-(+)-2-amino-1,2-diphenylethanol.

FIG. 22 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(1R,2S)-(−)-2-amino-1,2-diphenylethanol.

FIG. 23 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(1R,2S)-(−)-2-amino-1,2-diphenylethanol.

FIG. 24 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(+)-cis-2-benzylaminocyclohexanemethanol.

FIG. 25 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(+)-cis-2-benzylaminocyclohexanemethanol.

FIG. 26 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(−)-cis-2-benzylaminocyclohexanemethanol.

FIG. 27 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(−)-cis-2-benzylaminocyclohexanemethanol.

FIG. 28 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(S)-(−)-2-amino-3-phenyl-1-propanol.

FIG. 29 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(S)-(−)-2-amino-3-phenyl-1-propanol.

FIG. 30 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-2-amino-3-phenyl-1-propanol.

FIG. 31 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(R)-(+)-2-amino-3-phenyl-1-propanol.

FIG. 32 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(4-bromophenyl)ethylamine.

FIG. 33 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(4-bromophenyl)ethylamine.

FIG. 34 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylpropylamine.

FIG. 35 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and (R)-(+)-1-phenylpropylamine.

FIG. 36 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and1,2-diphenylethylamine.

FIG. 37 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and 1,2-diphenylethylamine.

FIG. 38 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and benzhydrylamine.

FIG. 39 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and benzhydrylamine.

FIG. 40 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and cyclohexylamine.

FIG. 41 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and cyclohexylamine.

FIG. 42 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and dicyclohexylamine.

FIG. 43 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and dicyclohexylamine.

FIG. 44 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine.

FIG. 45 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine.

FIG. 46 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and cycloheptylamine.

FIG. 47 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and cycloheptylamine.

FIG. 48 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid andN-ethylcyclohexylamine.

FIG. 49 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and N-ethylcyclohexylamine.

FIG. 50 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and2,2,6,6-tetramethyl-4-piperidinol.

FIG. 51 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and2,2,6,6-tetramethyl-4-piperidinol.

FIG. 52 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and2-(2-methoxyphenyl)ethylamine.

FIG. 53 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and 2-(2-methoxyphenyl)ethylamine.

FIG. 54 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and2-(3,4-dimethoxyphenyl)ethylamine.

FIG. 55 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and2-(3,4-dimethoxyphenyl)ethylamine.

FIG. 56 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid andN-isopropylbenzylamine.

FIG. 57 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and N-isopropylbenzylamine.

FIG. 58 shows a chart of powdered X-ray diffraction spectrum of acrystal comprising (2R)-2-propyloctanoic acid and N-butylbenzylamine.

FIG. 59 shows a chart of infrared absorption spectrum (IR) of a crystalcomprising (2R)-2-propyloctanoic acid and N-butylbenzylamine.

FIG. 60 shows a chart of powdered X-ray diffraction spectrum of calcium(2R)-2-propyloctanoate.

DETAILED DESCRIPTION

In the present invention, (2R)-2-propyloctanoic acid means a compound offormula (I):

wherein

indicates a β-configuration.

In the present invention, (2R)-2-propyloctanoic acid is not limited to apractically pure single material but includes a mixture of(2R)-2-propyloctanoic acid and (2S)-2-propyloctanoic acid of formula(II):

wherein

indicates an α-configuration,

that is, as far as (2R)-2-propyloctanoic acid is preferentiallycontained, it is defined as (2R)-2-propyloctanoic acid. In addition,(2R)-2-propyloctanoic acid may contain, for example, impurities such asby-product, solvent, raw material, or degradation product.

The content of these impurities is variable depending on the kind ofimpurities contained and the subsequent intended use, and there is nolimitation in the content, accordingly. When (2R)-2-propyloctanoic acidis used as a bulk drug for pharmaceuticals, the content is preferably,for example, about 20 ppm or lower for heavy metals, about 1.49% by massor less for (2S)-2-propyloctanoic acid, about 5000 ppm or less in totalfor the residual solvent 2-propanol or heptane, and about 0.2% by massor less for moisture.

(2R)-2-Propyloctanoic acid may be produced according to the per se knownprocesses as described in, for example, JP Patent 3032447, JP Patent3084345, EP Patent 0632008, EP Patent 1078921, U.S. Pat. No. 6,608,221,WO03/051852, WO03/097851, and WO04/110972; process as described inComprehensive Organic Transformations: A Guide to Functional GroupPreparation, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc.,1999); for example, according to the process as described in Examples asmentioned below; or in proper combination of those processes. Theresulting (2R)-2-propyloctanoic acid can be purified by a conventionalpurification method, for example, distillation under atmosphericpressure or reduced pressure, high performance liquid chromatographyusing silica gel or magnesium silicate, thin layer chromatography, orcolumn chromatography or washing.

The present invention discloses such a crystal comprising(2R)-2-propyloctanoic acid and an amine. In this specification, thecrystal means a solid material in which the constitutive molecules arearranged in three-dimensional periodism and which has approximately adefinite melting point and definite constitution.

In this invention, the amine may be in any type including opticallyactive amines and optically inactive amines, as far as it can form acrystal with (2R)-2-propyloctanoic acid. Herein, the optically activeamine means those having an optical rotating power, and the opticallyinactive amine means those having no optical rotating power. Thisclassification is not affected by the presence or absence of anasymmetric carbon. The racemates of amines are classified into anoptically inactive amines in this invention.

As for the amines in the present invention, for example, the followingamines are preferably used. All of those amines are known clearly asseen from the CAS number indicated in the parenthesis.

In the present invention, the optically active amine includespreferably, for example, (a-1) (+)-dehydroabietylamine [CAS:#1446-61-3], (a-2) (R)-(−)-2-phenylglycinol [CAS: #56613-80-0], (a-3)(S)-(+)-2-phenylglycinol [CAS: #20989-17-7], (a-4) (−)-cis-myrtanylamine[CAS: #38235-68-6], (a-5) (R)-(+)-1-(p-tolyl)ethylamine [CAS:#4187-38-6], (a-6) (R)-(+)-1-(1-naphthyl)ethylamine [CAS: #3886-70-2],(a-7) (S)-(−)-1-(1-naphthyl)ethylamine [CAS: #10420-89-0], (a-8)L-tyrosinamide [CAS: #4985-46-0], (a-9)(1S,2R)-(+)-2-amino-1,2-diphenylethanol [CAS: #23364-44-5], (a-10)(1R,2S)-(−)-2-amino-1,2-diphenylethanol [CAS: #23190-16-1], (a-11)(+)-cis-2-benzylaminocyclohexanemethanol [CAS: #71581-92-5], (a-12)(−)-cis-2-benzylaminocyclohexanemethanol [CAS: #71581-93-6], (a-13)(S)-(−)-2-amino-3-phenyl-1-propanol [CAS: #3182-95-6], (a-14)(R)-(+)-2-amino-3-phenyl-1-propanol [CAS: #5267-64-1], (a-15)(R)-(+)-1-(4-bromophenyl)ethylamine [CAS: #45791-36-4] and (a-16)(R)-(+)-1-phenylpropylamine [CAS: #3082-64-2].

In the present invention, the optically inactive amine includespreferably, for example, (b-1) dibenzylamine [CAS: #103-49-1], (b-2)1,2-diphenylethylamine [CAS: #25611-78-3], (b-3) benzhydrylamine [CAS:#911-00-9], (b-4) cyclohexylamine [CAS: #108-91-8], (b-5)dicyclohexylamine [CAS: #101-83-7], (b-6) cycloheptylamine [CAS:#5452-35-7], (b-7) N-ethylcyclohexylamine [CAS: #5459-93-8], (b-8)2,2,6,6-tetramethyl-4-piperidinol [CAS: #2403-88-5], (b-9)2-(2-methoxyphenyl)ethylamine [CAS: #2045-79-6], (b-10)2-(3,4-dimethoxyphenyl)ethylamine [CAS: #120-20-7], (b-11)N-isopropylbenzylamine [CAS: #102-97-6] and (b-12) N-butylbenzylamine[CAS: #2403-22-7].

The preferred amines used in the present invention are low toxic aminescontained in the pharmaceuticals approved by Food and DrugAdministration (FDA) in USA, with which active ingredients can formsalts.

The particularly preferred amine in the present invention includesdibenzylamine.

In the present invention, the crystal comprising (2R)-2-propyloctanoicacid and dibenzylamine (hereinafter sometimes referred to as “crystalwith dibenzylamine”) may be produced by a process as mentioned below.The crystal with dibenzylamine produced by such a process was a newcrystal comprising 2 molecules of (2R)-2-propyloctanoic acid and 1molecule of dibenzylamine, as seen clearly from the results of elementalanalysis as mentioned in Example below.

The crystal with dibenzylamine can be characterized by the followingdata. Specifically, the crystal is characterized by a chart (FIG. 1) ofpowdered X-ray diffraction spectrum obtained by irradiation of Cu—Kα rayor the diffraction angle (20) as shown in Table 1 below, the half widthand relative intensity. In the present invention, the relative intensityis represented by the rate of the peaks to the highest peak which isregarded as 100%.

TABLE 1 Crystal with dibenzylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 15.27 5.80 64.9 17.03 5.20 34.519.04 4.66 100.0 19.99 4.44 85.7 21.36 4.16 25.8 22.91 3.88 80.4 24.213.67 89.1 26.09 3.41 30.7 26.70 3.34 28.9 28.42 3.14 23.8 30.83 2.9024.6 34.06 2.63 22.3

The crystal with dibenzylamine can be characterized by a chart ofinfrared absorption (IR) spectrum measured by the KBr method (FIG. 2) orabsorption peaks of 3434, 3068, 3036, 2957, 2926, 2872, 2853, 2756,2621, 2454, 1948, 1638, 1498, 1466, 1457, 1415, 1379, 1342, 1321, 1212,1141, 1112, 1096, 1044, 989, 936, 905, 812, 763, 744 and 694 cm⁻¹.

Further, the crystal with dibenzylamine is also characterized by a chart(FIG. 3) of differential scanning calorimetry (DSC) or by an endothermicpeak at approximately 81.8° C.

The crystal with dibenzylamine is also characterized in that thespecific rotation [α]_(D)″ is about −3.6 (c=2.00; ethanol) when theoptical purity of the crystal is about 99.8% e.e.

The crystal with dibenzylamine disclosed in the present invention ischaracterized by the physicochemical properties as described herein, butthe data such as respective spectra or specific rotation should not beconstrued strictly because they are somewhat variable substantially.

For example, in the powdered X-ray diffraction spectra in confirming theidentity of crystals, the diffraction angle (2θ) or their overallpatterns are important, and the relative intensity is somewhat variabledepending on direction of crystal growth, size of particle, and thecondition of measurement. In IR spectra in confirming the identity ofcrystals, the overall patterns are important but somewhat variabledepending on the condition of measurement. Further, in DSC in confirmingthe identity of crystals, the overall patterns are important butsomewhat variable depending on the condition of measurement.

In addition, for example, the specific rotation is also variabledepending on the optical purity of crystal, concentration, solvent usedin measurement, temperature, the presence or absence of impurities, andso on.

Therefore, any crystal in which the data or chart pattern in thepowdered X-ray diffraction spectrum, IR spectrum and/or DSC aregenerally the same as that of the crystal with dibenzylamine or showsthe same specific rotation, is included in the crystal withdibenzylamine of the present invention.

In the present invention, the crystal comprising (2R)-2-propyloctanoicacid and an amine of the above (a-1) to (a-16) or (b-2) to (b-12) may beproduced according to the process as mentioned below. The crystals withamines produced according to such a process, all are new crystals.

These crystals can be characterized by the following data. Specifically,the crystal is characterized by a chart of powdered X-ray diffractionspectrum obtained by irradiation of Cu—Kα ray (FIG. 4, FIG. 6, FIG. 8,FIG. 10, FIG. 12, FIG. 14, FIG. 16, FIG. 18, FIG. 20, FIG. 22, FIG. 24,FIG. 26, FIG. 28, FIG. 30, FIG. 32, FIG. 34, FIG. 36, FIG. 38, FIG. 40,FIG. 42, FIG. 46, FIG. 48, FIG. 50, FIG. 52, FIG. 54, FIG. 56, FIG. 58)or the diffraction angle (2θ) as shown in Table 2 to Table 25 below, thehalf width and relative intensity.

TABLE 2 Crystal with (+)-dehydroabietylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 12.16 7.27 15.2 12.90 6.8614.2 14.04 6.30 17.1 15.15 5.84 88.6 15.70 5.64 40.2 16.46 5.38 32.417.08 5.19 63.7 18.35 4.83 100.0 18.96 4.68 44.3 19.45 4.56 44.2 20.564.32 67.1 22.31 3.98 26.9 23.35 3.81 25.5 24.44 3.64 37.5 25.65 3.4724.8

TABLE 3 Crystal with (−)-cis-myrtanylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 11.23 7.88 6.3 14.53 6.09 19.615.43 5.74 21.4 16.55 5.35 87.6 17.74 5.00 100.0 18.71 4.74 56.0 19.574.53 56.4 21.44 4.14 45.9 22.45 3.96 22.2 23.29 3.82 11.2 24.45 3.6416.1 25.60 3.48 18.7 26.57 3.35 14.1 27.20 3.28 16.4 27.50 3.24 16.029.74 3.00 13.6 31.20 2.86 16.1 32.92 2.72 12.6 34.22 2.62 12.1 35.792.51 8.7 36.59 2.45 9.7

TABLE 4 Crystal with (R)-(+)-1-(p-tolyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 11.34 7.79 24.412.01 7.36 8.7 12.81 6.91 31.7 13.69 6.46 6.7 15.08 5.87 8.8 16.15 5.4845.5 17.47 5.07 20.9 18.84 4.71 100.0 20.08 4.42 28.2 20.68 4.29 71.722.03 4.03 19.3 23.00 3.86 89.2 24.14 3.68 27.1 25.65 3.47 54.2 27.413.25 29.2 28.22 3.16 17.1 29.92 2.98 14.6 30.99 2.88 14.0 32.64 2.7415.6 33.22 2.70 14.6 34.46 2.60 12.3

TABLE 5 Crystal with (R)-(+)-1-(1-naphthyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 10.97 8.06 14.413.38 6.61 58.1 15.84 5.59 48.9 16.91 5.24 31.0 17.67 5.02 40.8 19.314.59 54.2 20.46 4.34 34.3 21.52 4.13 43.2 22.21 4.00 100.0 23.49 3.7867.5 24.41 3.64 24.2 25.11 3.54 24.1 26.78 3.33 22.7 28.12 3.17 14.728.96 3.08 21.3 31.28 2.86 20.6 33.79 2.65 13.8 35.87 2.50 12.9 36.772.44 12.4

TABLE 6 Crystal with (S)-(−)-1-(1-naphthyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 12.41 7.13 22.813.71 6.45 24.6 14.05 6.30 20.6 15.12 5.86 41.4 16.27 5.45 35.1 16.805.27 54.0 17.57 5.04 57.3 18.72 4.74 53.3 19.35 4.58 94.0 19.96 4.4557.4 21.00 4.23 74.1 21.50 4.13 57.6 22.41 3.96 100.0 23.56 3.77 27.523.95 3.71 28.0 25.55 3.48 49.7 26.21 3.40 41.1 27.79 3.21 32.9 28.563.12 25.9 30.92 2.89 26.0

TABLE 7 Crystal with L-tyrosinamide Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 12.10 7.31 10.7 12.83 6.89 8.7 14.676.03 15.3 15.44 5.73 17.4 16.46 5.38 57.5 17.08 5.19 100.0 18.19 4.8740.7 19.89 4.46 91.5 21.30 4.17 66.1 22.12 4.02 40.1 23.31 3.81 61.624.15 3.68 48.1 25.81 3.45 37.5 27.36 3.26 43.0 28.66 3.11 20.8 29.852.99 19.7 30.95 2.89 23.2 32.97 2.71 29.2 33.48 2.67 21.9 35.00 2.5617.7 36.64 2.45 20.7

TABLE 8 Crystal with (1S,2R)-(+)-2-amino-1,2-diphenylethanol Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 13.60 6.5125.5 14.18 6.24 20.4 15.96 5.55 100.0 17.33 5.11 44.1 18.35 4.83 22.519.47 4.56 62.7 20.46 4.34 82.6 21.41 4.15 59.3 22.45 3.96 37.5 23.553.77 64.9 24.78 3.59 61.9 25.97 3.43 25.8 27.53 3.24 22.8 28.63 3.1219.6 29.79 3.00 24.1 32.31 2.77 16.5 33.54 2.67 20.2 35.51 2.53 21.9

TABLE 9 Crystal with (1R,2S)-(−)-2-amino-1,2-diphenylethanol Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 10.06 8.79 8.911.94 7.41 21.5 12.88 6.87 8.8 15.11 5.86 37.0 15.97 5.54 73.4 16.525.36 44.3 17.91 4.95 89.4 19.15 4.63 55.9 19.77 4.49 80.0 21.29 4.1783.6 23.04 3.86 100.0 24.07 3.69 36.8 25.40 3.50 59.4 25.76 3.46 58.228.44 3.14 27.0 29.57 3.02 23.2 30.70 2.91 27.4 35.72 2.51 26.0

TABLE 10 Crystal with (+)-cis-2-benzylaminocyclohexanemethanolDiffraction angle (2θ) Half width Relative intensity (degree) (Å) (%)10.49 8.43 6.5 12.01 7.36 9.8 13.37 6.62 5.2 15.92 5.56 14.1 16.68 5.3118.7 17.90 4.95 100.0 19.83 4.47 28.8 21.16 4.20 34.2 22.75 3.91 13.924.34 3.65 9.4 26.06 3.42 12.5 27.68 3.22 13.5 28.56 3.12 10.8 30.372.94 9.9 32.05 2.79 11.1

TABLE 11 Crystal with (−)-cis-2-benzylaminocyclohexanemethanolDiffraction angle (2θ) Half width Relative intensity (degree) (Å) (%)10.01 8.83 6.9 12.38 7.15 28.3 15.35 5.77 24.7 16.29 5.44 27.7 17.994.93 100.0 19.02 4.66 39.6 20.00 4.44 68.1 21.52 4.13 23.5 21.85 4.0628.8 22.84 3.89 24.8 23.93 3.71 15.3 24.87 3.58 21.4 25.46 3.50 27.228.03 3.18 21.2 29.91 2.99 17.5 31.21 2.86 16.7 35.00 2.56 11.3 35.892.50 13.1

TABLE 12 Crystal with (R)-(+)-2-amino-3-phenyl-1-propanol Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 8.29 10.66 5.110.15 8.71 5.2 13.33 6.64 12.0 15.94 5.56 31.2 16.61 5.33 24.8 17.874.96 23.1 19.83 4.47 100.0 21.48 4.13 41.0 24.51 3.63 14.7 26.22 3.4027.5 27.48 3.24 17.4 30.09 2.97 19.8 32.33 2.77 11.6 33.73 2.66 10.636.36 2.47 10.8

TABLE 13 Crystal with (R)-(+)-1-(4-bromophenyl)ethylamine Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 9.47 9.33 16.211.43 7.74 23.8 12.02 7.36 27.5 15.06 5.88 33.5 16.10 5.50 23.1 17.455.08 21.5 19.00 4.67 100.0 20.17 4.40 47.4 20.69 4.29 34.0 22.01 4.0451.5 23.12 3.84 82.2 24.11 3.69 68.3 25.55 3.48 46.5 27.43 3.25 62.729.75 3.00 44.1 32.38 2.76 35.8 34.67 2.59 32.7 35.94 2.50 31.5

TABLE 14 Crystal with (R)-(+)-1-phenylpropylamine Diffraction angle (2θ)Half width Relative intensity (degree) (Å) (%) 12.49 7.08 28.2 13.986.33 17.6 14.44 6.13 42.9 15.63 5.66 15.1 16.38 5.41 15.1 18.50 4.7924.7 19.18 4.62 51.2 20.53 4.32 20.6 21.17 4.19 72.8 21.76 4.08 100.022.61 3.93 39.7 23.35 3.81 36.6 24.23 3.67 52.0 25.36 3.51 52.3 26.463.37 16.1 28.22 3.16 13.3 28.81 3.10 18.7 29.75 3.00 17.2 30.62 2.9215.6 31.41 2.85 12.3 32.45 2.76 13.2 33.49 2.67 11.5 35.16 2.55 14.735.72 2.51 15.0

TABLE 15 Crystal with 1,2-diphenylethylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 12.38 7.14 12.3 13.37 6.6225.1 14.04 6.30 18.2 16.50 5.37 56.3 17.73 5.00 100.0 18.80 4.72 77.819.83 4.47 77.3 21.17 4.19 34.2 22.80 3.90 44.5 24.07 3.69 41.2 25.143.54 40.0 27.06 3.29 29.8 28.35 3.15 20.0 29.25 3.05 18.5 30.66 2.9118.6

TABLE 16 Crystal with benzhydrylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 13.58 6.52 8.6 14.50 6.11 13.5 16.055.52 15.4 16.85 5.26 43.4 18.38 4.82 42.9 19.27 4.60 60.7 21.28 4.17100.0 21.63 4.10 76.2 22.70 3.91 42.5 23.46 3.79 52.0 24.59 3.62 21.225.85 3.44 35.0 26.48 3.36 40.7 26.93 3.31 27.8 28.31 3.15 19.5 30.032.97 15.9 31.38 2.85 17.5 33.55 2.67 15.8 36.60 2.45 15.3

TABLE 17 Crystal with cyclohexylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 10.98 8.05 8.9 11.37 7.77 11.6 12.846.89 18.0 14.68 6.03 15.2 15.86 5.58 33.3 17.03 5.20 39.0 17.62 5.0342.1 18.82 4.71 100.0 20.09 4.42 54.8 20.90 4.25 71.7 21.83 4.07 75.922.54 3.94 35.6 25.40 3.50 25.2 25.98 3.43 26.5 27.91 3.19 19.8 29.073.07 21.4 30.03 2.97 21.5 31.64 2.83 18.8 33.24 2.69 16.0 35.89 2.5017.5

TABLE 18 Crystal with dicyclohexylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 11.16 7.92 12.3 12.22 7.24 5.914.59 6.07 8.6 15.30 5.78 14.6 16.75 5.29 19.1 18.28 4.85 35.2 19.134.64 100.0 19.80 4.48 38.1 21.27 4.17 25.0 22.42 3.96 26.1 23.51 3.7825.9 25.20 3.53 20.3 30.38 2.94 12.4 31.17 2.87 15.4 33.03 2.71 12.9

TABLE 19 Crystal with cycloheptylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 7.98 11.07 26.6 12.29 7.20 20.714.68 6.03 22.2 16.19 5.47 16.3 17.39 5.10 29.1 18.34 4.83 71.6 19.074.65 86.4 20.01 4.43 100.0 20.98 4.23 28.7 22.05 4.03 22.8 24.19 3.6821.5 25.56 3.48 21.7 27.02 3.30 22.0 30.80 2.90 21.4 32.65 2.74 23.1

TABLE 20 Crystal with N-ethylcyclohexylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 7.70 11.47 100.0 9.27 9.53 8.912.09 7.31 8.4 14.09 6.28 7.7 14.60 6.06 10.7 15.21 5.82 7.2 16.62 5.335.2 17.85 4.96 15.0 18.19 4.87 8.5 19.82 4.48 23.2 20.78 4.27 16.6 21.744.09 10.6 22.61 3.93 9.4 23.42 3.80 8.8 25.09 3.55 8.2

TABLE 21 Crystal with 2,2,6,6-tetramethyl-4-piperidinol Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 9.11 9.70100.0 13.47 6.57 16.3 14.84 5.96 9.2 17.25 5.14 25.8 18.18 4.88 17.919.93 4.45 21.8 21.24 4.18 19.7 22.30 3.98 14.6 23.80 3.74 11.8 24.783.59 11.0 25.96 3.43 11.5 30.28 2.95 8.5

TABLE 22 Crystal with 2-(2-methoxyphenyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 9.56 9.25 16.1 12.267.21 30.0 13.28 6.66 18.3 13.93 6.35 27.0 15.34 5.77 53.4 15.99 5.5435.3 16.50 5.37 32.5 17.31 5.12 23.5 18.57 4.77 32.3 19.15 4.63 58.620.04 4.43 100.0 20.74 4.28 90.6 21.65 4.10 69.2 23.52 3.78 44.1 24.483.63 35.2 25.76 3.46 37.7 26.35 3.38 45.4 27.52 3.24 28.1 29.20 3.0634.4 30.87 2.89 16.7 32.10 2.79 17.0 35.28 2.54 17.1

TABLE 23 Crystal with 2-(3,4-dimethoxyphenyl)ethylamine Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 8.56 10.3215.3 10.44 8.47 17.8 11.98 7.38 7.7 14.64 6.05 15.0 15.34 5.77 23.616.88 5.25 28.3 18.73 4.73 11.9 19.17 4.63 10.3 20.57 4.31 96.5 22.054.03 21.6 22.95 3.87 100.0 25.22 3.53 19.2 27.65 3.22 9.5 29.07 3.07 8.032.33 2.77 7.8

TABLE 24 Crystal with N-isopropylbenzylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 7.97 11.08 100.0 11.34 7.8019.8 12.91 6.85 11.8 13.36 6.62 7.8 15.27 5.80 16.1 17.21 5.15 30.117.68 5.01 18.8 18.83 4.71 39.2 20.06 4.42 19.3 21.88 4.06 44.2 23.293.82 21.2 24.01 3.70 15.9 26.76 3.33 11.4 27.67 3.22 9.5 31.83 2.81 8.832.94 2.72 9.1

TABLE 25 Crystal with N-butylbenzylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 11.71 7.55 10.1 13.84 6.3912.8 19.81 4.48 38.2 20.67 4.29 100.0 24.64 3.61 22.3

These crystals are characterized by the chart of IR spectra measured bythe ATR method (FIG. 5, FIG. 7, FIG. 9, FIG. 11, FIG. 13, FIG. 15, FIG.17, FIG. 19, FIG. 21, FIG. 23, FIG. 25, FIG. 27, FIG. 29, FIG. 31, FIG.33, FIG. 35, FIG. 37, FIG. 39, FIG. 41, FIG. 43, FIG. 47, FIG. 49, FIG.51, FIG. 53, FIG. 55, FIG. 57, FIG. 59) and the following absorptionpeaks.

(a-1) Crystal with (+)-dehydroabietylamine:2954, 2925, 2850, 2663, 2197, 1560, 1534, 1497, 1456, 1436, 1394, 1360,1298, 1210, 1173, 1147, 1109, 1056, 1005, 911, 883, 854, 822, 777, 752,726, 674, 630 cm⁻¹.(a-2) Crystal with (R)-(−)-2-phenylglycinol:3034, 2953, 2926, 2854, 2668, 2509, 2143, 1640, 1605, 1522, 1457, 1400,1376, 1339, 1316, 1281, 1228, 1207, 1186, 1119, 1065, 1049, 994, 919,891, 854, 787, 758, 700, 537 cm⁻¹.(a-3) Crystal with (S)-(+)-2-phenylglycinol:3033, 2953, 2925, 2870, 2850, 2670, 2516, 2155, 1641, 1567, 1524, 1496,1457, 1433, 1393, 1308, 1208, 1182, 1149, 1112, 1067, 1054, 1030, 1000,920, 893, 860, 801, 758, 701 cm⁻¹.(a-4) Crystal with (−)-cis-myrtanylamine:2989, 2952, 2919, 2869, 2852, 2611, 2196, 1626, 1517, 1458, 1397, 1363,1320, 1230, 1214, 1139, 1116, 1035, 1005, 978, 919, 874, 848, 809, 779,747, 721, 637 cm⁻¹.(a-5) Crystal with (R)-(+)-1-(p-tolyl)ethylamine:2954, 2925, 2856, 2702, 2536, 2210, 1621, 1567, 1518, 1464, 1440, 1405,1381, 1315, 1306, 1231, 1172, 1111, 1090, 1021, 993, 898, 868, 849, 813,779, 744, 722, 685 cm⁻¹.(a-6) Crystal with (R)-(+)-1-(1-naphthyl)ethylamine:2952, 2924, 2854, 2759, 2582, 2180, 1629, 1571, 1509, 1467, 1454, 1433,1402, 1389, 1378, 1335, 1305, 1275, 1253, 1231, 1173, 1110, 1076, 1004,950, 900, 860, 801, 774 cm⁻¹.(a-7) Crystal with (S)-(−)-1-(1-naphthyl)ethylamine:2952, 2922, 2850, 2219, 1624, 1601, 1557, 1514, 1467, 1454, 1395, 1377,1317, 1279, 1223, 1177, 1108, 1075, 1030, 1002, 950, 923, 898, 860, 849,799, 775, 749 cm⁻¹.(a-8) Crystal with L-tyrosinamide:3430, 2953, 2923, 2856, 1673, 1559, 1512, 1449, 1407, 1376, 1349, 1324,1266, 1242, 1210, 1175, 1108, 1078, 1037, 997, 850, 830, 785, 736, 645cm⁻¹.(a-9) Crystal with (1S,2R)-(+)-2-amino-1,2-diphenylethanol:2925, 2851, 1617, 1559, 1507, 1455, 1406, 1320, 1272, 1204, 1134, 1081,1047, 1007, 919, 848, 782, 765, 742, 699, 567 cm⁻¹.(a-10) Crystal with (1R,2S)-(−)-2-amino-1,2-diphenylethanol:3275, 2953, 2925, 2856, 2605, 1617, 1560, 1542, 1508, 1455, 1408, 1307,1277, 1239, 1205, 1132, 1110, 1081, 1046, 1006, 921, 907, 849, 811, 783,765, 742, 700 cm⁻¹.(a-11) Crystal with (+)-cis-2-benzylaminocyclohexanemethanol:3034, 2951, 2926, 2853, 1622, 1526, 1498, 1450, 1406, 1341, 1310, 1261,1218, 1141, 1117, 1087, 1063, 1051, 1034, 1013, 974, 914, 862, 841, 812,785, 750, 696, 645 cm⁻¹.(a-12) Crystal with (−)-cis-2-benzylaminocyclohexanemethanol:3033, 2949, 2925, 2854, 1622, 1524, 1497, 1454, 1397, 1341, 1324, 1261,1219, 1115, 1087, 1075, 1061, 1037, 1010, 975, 914, 781, 750, 697, 634cm⁻¹.(a-13) Crystal with (S)-(−)-2-amino-3-phenyl-1-propanol:3241, 3029, 2953, 2925, 2853, 2546, 2163, 1623, 1576, 1541, 1497, 1456,1398, 1374, 1338, 1285, 1206, 1175, 1113, 1093, 1065, 1031, 997, 944,915, 850, 806, 740, 697 cm⁻¹.(a-14) Crystal with (R)-(+)-2-amino-3-phenyl-1-propanol:3255, 3065, 3030, 2954, 2925, 2854, 2547, 2153, 1622, 1574, 1541, 1496,1456, 1395, 1375, 1338, 1309, 1279, 1207, 1175, 1113, 1093, 1065, 1031,997, 945, 913, 850, 787, 740, 697 cm⁻¹.(a-15) Crystal with (R)-(+)-1-(4-bromophenyl)ethylamine:2954, 2925, 2855, 2703, 2195, 1621, 1571, 1515, 1491, 1466, 1440, 1404,1381, 1306, 1281, 1231, 1186, 1110, 1090, 1011, 898, 850, 832, 819, 779,742, 725, 716, 686 cm⁻¹.(a-16) Crystal with (R)-(+)-1-phenylpropylamine:2950, 2926, 2855, 2665, 2215, 1622, 1561, 1525, 1457, 1436, 1400, 1380,1329, 1297, 1274, 1214, 1185, 1153, 1110, 1032, 998, 913, 892, 849, 778,760, 750, 741, 695, 673 cm⁻¹.(b-2) Crystal with 1,2-diphenylethylamine:3030, 2953, 2925, 2852, 2663, 2176, 1627, 1536, 1497, 1467, 1455, 1431,1396, 1338, 1310, 1275, 1232, 1110, 1074, 1024, 976, 935, 910, 846, 795,775, 758, 740, 697 cm⁻¹.(b-3) Crystal with benzhydrylamine:2995, 2925, 2853, 2614, 2194, 1617, 1573, 1519, 1497, 1457, 1446, 1395,1303, 1226, 1198, 1151, 1075, 1032, 1010, 998, 917, 837, 809, 755, 735,695, 641, 542 cm⁻¹.(b-4) Crystal with cyclohexylamine:2922, 2855, 2625, 2569, 2224, 1634, 1525, 1455, 1399, 1340, 1313, 1285,1246, 1140, 1115, 1073, 1050, 920, 891, 849, 801, 780, 748, 641, 554cm⁻¹.(b-5). Crystal with dicyclohexylamine:2926, 2853, 1622, 1524, 1488, 1455, 1401, 1352, 1306, 1253, 1186, 1113,1084, 1064, 1037, 980, 921, 887, 849, 805, 758, 640, 596 cm⁻¹.(b-6) Crystal with cycloheptylamine:2924, 1624, 1523, 1457, 1396 cm⁻¹.(b-7) Crystal with N-ethylcyclohexylamine:2925, 1622, 1531, 1449, 1402 cm⁻¹.(b-8) Crystal with 2,2,6,6-tetramethyl-4-piperidinol:3272, 2927, 1605, 1522 cm⁻¹.(b-9) Crystal with 2-(2-methoxyphenyl)ethylamine:2921, 1634, 1494, 1242 cm⁻¹.(b-10) Crystal with 2-(3,4-dimethoxyphenyl)ethylamine:2920, 1515, 1449, 1402, 1237 cm⁻¹.(b-11) Crystal with N-isopropylbenzylamine:2926, 1529, 1442, 1401 cm⁻¹.(b-12) Crystal with N-butylbenzylamine:2925, 1545, 1458, 1398 cm⁻¹.

The crystals with the above (a-1) to (a-16) or (b-2) to (b-12) are alsocharacterized by their physicochemical properties as described herein inthe same way as in the above crystal with dibenzylamine, but thespectral data should not be construed strictly because they are somewhatvariable substantially.

The crystal comprising (2R)-2-propyloctanoic acid and an amine obtainedin the present invention is per se excellent in availability as a bulkdrug of pharmaceuticals since it is (1) stable as a material, (2)possible to stably supply in large quantities, and/or (3) relativelyreadily convertible into a pharmaceutical preparation such as tablets.

Pharmaceutical compositions in which these crystals can be used as bulkdrugs include, for example, solid compositions for oral administration,liquid compositions for oral administration, injections, agents forexternal use and suppositories for parenteral administration, and thelike. Particularly, solid compositions such as solid compositions fororal administration, agents for external use and suppositories arepreferable by utilizing such characterization that solids as crystalscan be obtained.

Solid compositions for oral administration include tablets, pills,capsules, dispersible powders, granules and the like. Capsules includehard capsules and soft capsules.

The solid composition for oral administration is used by formulating acrystal comprising (2R)-2-propyloctanoic acid and amine (hereinafterreferred to as “active compounds”) as it is or as a mixture with anexcipient (e.g., lactose, mannitol, glucose, microcrystalline cellulose,starch, etc.), a binding agent (e.g., hydroxypropylcellulose,polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), adisintegrating agent (e.g., calcium disodiumethylenediaminetetraacetate, etc.), a lubricant (e.g., magnesiumstearate, etc.), a stabilizer (e.g., antioxidant (e.g., sulfite, sodiumpyrosulfife, ascorbic acid, etc.), etc.), a solubilizer (e.g., glutamicacid, aspartic acid, polysorbates (e.g., POLYSORBATE 20, POLYSORBATE 60,POLYSORBATE 65, POLYSORBATE 80, etc.), macrogols (e.g., MACROGOL 200,MACROGOL 400, MACROGOL 1000, MACROGOL 1500, MACROGOL 4000, MACROGOL6000, MACROGOL 20000, etc.), ethanol, glycerine, carboxymethylcellulose, etc.) or the like according to the generally used methods.Also, if necessary, they may be coated with a coating agent (e.g.,sugar, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulosephthalate, etc.), or be coated with two or more films. Moreover,capsules of absorbable materials such as gelatin are included.

Liquid compositions for oral administration include pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups, elixirs and thelike. In such liquid compositions, one or more of the active compoundsmay be dissolved, suspended or emulsified into diluent(s) commonly usedin the art (such as purified water, ethanol, a mixture thereof, etc.).Besides such liquid forms may also comprise some additives, such aswetting agents, suspending agents, emulsifying agents, sweeteningagents, flavoring agents, aroma, preservative or buffering agent.

Injections for parenteral administration include solutions, suspensionsand emulsions, solid injections which are to be dissolved or suspendedin solvents upon use, and the like. The injections are prepared bydissolving, suspending or emulsifying the active substances in asolvent. Examples of the solvent include distilled water for injection,physiological saline, plant oil, alcohols such as propylene glycol,polyethylene glycol and ethanol, combinations thereof, and the like.Further, the injection may contain a stabilizer (e.g., antioxidant(e.g., sulfite, sodium pyrosulfife, ascorbic acid, etc.), etc.), asolubilizer (e.g., glutamic acid, arpartic acid, polysorbates (e.g.,POLYSORBATE 20, POLYSORBATE 60, POLYSORBATE 65, POLYSORBATE 80, etc.),macrogols (e.g., MACROGOL 200, MACROGOL 400, MACROGOL 1000, MACROGOL1500, MACROGOL 4000, MACROGOL 6000, MACROGOL 20000, etc.), ethanol,glycerine, carboxymethyl cellulose, etc.), a solubilizing auxiliaryagent such as glutamic acid, aspartic acid and POLYSORBATE 80(registered trade mark) etc.), a pH adjusting agent (e.g., hydrochloricacid, citric acid, sodium citrate, acetic acid, tartaric acid, succinicacid, arginine, monoethanolamine, monoethanolamine, triethanolamine,meglumine, sodium hydroxide, potassium hydroxide, sodium bicarbonate,sodium carbonate, etc.), a suspending agent, an emulsifying agent, asoothing agent (e.g., chlorobutanol, creatinine, inositol, etc.), abuffering agent (e.g., phosphoric acid, trisodium phosphate, dibasicsodium phosphate, dibasic potassium phosphate, potassium dihydrogenphosphate, sodium dihydrogen phosphate, etc.), a preservative agent(e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propylparahydroxybenzoate, butyl methyl parahydroxybenzoate, etc.) and thelike. The injection may be sterilized in the final step of thepreparation process or the whole preparation process may be preparedunder sterile conditions. The liquid injection may be used as it is ormay be used by dissolving it in an appropriate solvent (e.g., distilledwater for injection, physiological saline, various infusions, etc.).Also, the solid injection(e.g., freeze-dry product, etc.) is used bydissolving it in a solvent (e.g., distilled water for injection,physiological saline, carbohydrate solution, etc.) upon use, and ifdesired, by further diluting it by an appropriate medium for dilution(e.g., distilled water for injection, physiological saline, variousinfusions, etc.).

The agents for external use for parenteral administration include, forexample, ointments, gels, creams, poultices, adhesive preparations,liniments, air sprays, inhalants, sprays, eye-drops, nasal-drops and thelike. The agents for external use can be prepared by formulating theactive substance by a known method or a generally used formulationmethod.

Other compositions for parenteral administration include suppositoriesfor intrarectal administration, pessaries for intravaginaladministration, and the like. These preparations can be prepared byformulating the active substance by a known method or a generally usedformulation method.

Process for Production of the Compounds of the Present Invention:

The crystal comprising (2R)-2-propyloctanoic acid and an amine in thepresent invention (hereinafter abbreviated to crystal of the presentinvention) can be produced by the process as mentioned below, or itsrelative process, or the process as described in Examples.

The crystal of the present invention can be produced by dissolving(2R)-2-propyloctanoic acid in water and/or an organic solvent [forexample, alcohol solvent (e.g., methanol, ethanol, isopropyl alcohol,etc.), ether solvent (e.g., diethyl ether, methyl t-butyl ether,dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran,1,4-dioxane, etc.), ketone solvent (e.g., acetone, 2-butanone, etc.),ester solvent (e.g., ethyl acetate, diethyl carbonate, etc.), nitrilesolvent (e.g., acetonitrile, etc.), aliphatic hydrocarbon solvent (e.g.,n-hexane, n-heptane, cyclohexane, etc.), aromatic hydrocarbon solvent(e.g., benzene, toluene, xylene, etc.) and the like, and a mixture ofthem at an optional ratio], adding about 0.5-about 1.1 equivalent of theabove amine, then stirring the resulting mixture at a temperature ofabout 40 to about 100° C. for a period of about 5 minutes to about 60minutes, then cooling it at a temperature of about −20 to about 20° C.,and stirring it at the same temperature for a period of about 5 to about60 minutes to yield precipitate. The precipitated crystals are collectedby filtration, washed with the above solvent, and dried to give theobjective crystals.

Since (2R)-2-propyloctanoic acid is an oil, this is mixed with the aboveamine without using any solvent, and the mixture is treated in the samemanner as described above to give the objective crystal of the presentinvention.

The (2R)-2-propyloctanoic acid used in production of the crystal as astarting material in the present invention is a known compound, and canbe produced by the known processes as described in, for example, JPPatent 3032447, JP Patent 3084345, EP Patent 0632008, EP Patent 1078921,U.S. Pat. No. 6,608,221, WO03/051852, WO03/097851, and WO04/110972; oraccording to the process as described in Examples as mentioned below; orin proper combination of those processes.

Furthermore, in the present invention, a process for producing anoptically highly pure (2R)-2-propyloctanoic acid is disclosed. In such aprocess, the crystal with dibenzylamine, among the crystals comprising(2R)-2-propyloctanoic acid and amines, may be used. That is, the crystalis per se useful as a bulk drug in production of pharmaceuticals asmentioned above, and also useful as an intermediate for obtainingoptically highly pure (2R)-2-propyloctanoic acid.

Such a process, i.e. process for producing optically highly pure(2R)-2-propyloctanoic acid using the crystal with dibenzylamine as anintermediate, may be carried out as follows.

That is, (2R)-2-propyloctanoic acid as a starting material and anoptically inactive amine (for example, dibenzylamine) are dissolved in asolvent to give a solution, which is applied to the following steps (1)to (3):

(1) a step of preferentially crystallizing the crystal comprising(2R)-2-propyloctanoic acid and an optically inactive amine out of thesolution;

(2) a step of separating and collecting the precipitated crystal;

(3) a step of dissolving the crystal in a solvent to give a solution.

This process is repeated with optional frequency to preferentiallycrystallizing the crystal comprising (2R)-2-propyloctanoic acid and theoptically inactive amine, from which crystal (2R)-2-propyloctanoic acidis recovered in a free form. When the steps (1) to (3) are repeated inoptional frequency, such an operation is sometimes regarded asrecrystallization. The recrystallization may be repeated again andagain, but in view of efficiency it may preferably be repeated 0 to 5times, more preferably 0 to 3 times and particularly 0 to 1 time.

One specific example of these steps is described in Example below, butin general, the step may be carried out as follows. In this connection,all the step specifically not indicated below may be carried outaccording to the known process.

First, the procedure for dissolving (2R)-2-propyloctanoic acid as astarting material and an optically inactive amine (e.g., dibenzylamine)in a solvent to give a solution, may be carried out as mentioned aboveby dissolving (2R)-2-propyloctanoic acid as a starting material andabout 0.5 to about 1.1 equivalent of an optically inactive amine (e.g.,dibenzylamine) in water and/or an organic solvent [for example, alcoholsolvent (e.g., methanol, ethanol, isopropyl alcohol, etc.), ethersolvent (e.g., diethyl ether, methyl t-butyl ether, dimethoxyethane,diethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, etc.),ketone solvent (e.g., acetone, 2-butanone, etc.), ester solvent (e.g.,ethyl acetate, diethyl carbonate, etc.), nitrile solvent (e.g.,acetonitrile, etc.), aliphatic hydrocarbon solvent (e.g., n-hexane,n-heptane, cyclohexane, etc.), aromatic hydrocarbon solvent (e.g.,benzene, toluene, xylene, etc.) or a mixture of these solvents at anoptional rate]. The (2R)-2-propyloctanoic acid used as a startingmaterial may be used in an optical purity of about 50% e.e. or more.Preferably, (2R)-2-propyloctanoic acid may be used in an optical purityof about 70% e.e. or more, more preferably in about 80% e.e. or more,particularly, about 90% e.e. or more.

The step of preferentially crystallizing the crystal out of the solutionis carried out in the same manner as above by stirring the solution at atemperature of about 40 to about 100° C. for a period of about 5 toabout 60 minutes, followed by cooling to about −20° C. to 20° C. andcontinuing the stirring for about 5 to about 60 minutes. Whendibenzylamine is used as an amine, in this step, the crystal comprising(2R)-2-propyloctanoic acid and dibenzylamine can be crystallizedpreferentially to the crystal comprising (2S)-2-propyloctanoic acid anddibenzylamine (preferential crystallization). Thus, much more opticallypure (2R)-2-propyloctanoic acid, preferably of the optical purity ofover 99.5% e.e., than the starting (2R)-2-propyloctanoic acid, can beobtained by separating a free form of (2R)-2-propyloctanoic acid.

Separation of the free form of (2R)-2-propyloctanoic acid from theisolated crystal of (2R)-2-propyloctanoic acid with an amine (e.g.,dibenzylamine) may be conducted, for example, according to the followingknown method.

That is, an aqueous solution of about 1 to about 5 equivalent ofinorganic base (e.g., potassium hydroxide, sodium hydroxide, lithiumhydroxide, calcium hydroxide, etc.) is waded to the crystal, and themixture is stirred for a period of about 5 to about 30 minutes and thenback-extracted with addition of an organic solvent [for example, ethersolvent (e.g., diethyl ether, methyl t-butyl ether, etc.), ester solvent(e.g., ethyl acetate, isopropyl acetate, diethyl carbonate, etc.),aliphatic hydrocarbon solvent (e.g., n-hexane, n-heptane, cyclohexane,etc.), or a mixture of them at an optional rate]. The resulting aqueouslayer is acidified with addition of an inorganic acid (e.g.,hydrochloric acid, sulfuric acid, etc.) at about 0 to about 20° C. andextracted with an extraction solvent [for example, ether solvent (e.g.,diethyl ether, methyl t-butyl ether, etc.), ester solvent (e.g., ethylacetate, isopropyl acetate, diethyl carbonate, etc.), aliphatichydrocarbon solvent (e.g., n-hexane, n-heptane, cyclohexane, etc.), or amixture of them at an optional rate]. Thus resulting organic layer iswashed, concentrated, and purified to give a free form of(2R)-2-propyloctanoic acid.

It is very important to obtain an optically highly pure compound (bulkdrug) in development of pharmaceuticals, and the purity is required tobe close to 100% without limit. Therefore, it is a very importantproblem in development of pharmaceuticals to find a process forenhancing the optical purity and an intermediate for use in such aprocess.

In general, it is well known that a carboxyl-containing compound whichcontains its racemate or its R-isomer or S-isomer preferentially can becrystallized with an optically active amine to increase the opticalpurity. For example, (2R)-2-propyloctanoic acid is known to be opticallypurified by using an optically active (R)-(+)-1-phenylethylamine (see:WO03/051852 pamphlet). It cannot be expected by a person skilled in theart, however, to increase the optical purity of a material using anoptically inactive amine as shown in the present invention, that is, toincrease the optical purity of a 2-propyloctanoic acid containingpreferentially an R-isomer, i.e., (2R)-2-propyloctanoic acid, up to99.5% e.e. or more by preferential crystallization with an opticallyinactive amine.

Moreover, as shown in Example below, the effect of improving the opticalpurity of (2R)-2-propyloctanoic acid of 95.0% e.e. was examined with(R)-(+)-1-phenylethylamine and dibenzylamine for comparison; as aresult, it was found that (R)-(+)-1-phenylethylamine required 7 timesrecrystallization to give (2R)-2-propyloctanoic acid with the opticalpurity of 99.5% e.e., but dibenzylamine required only twicerecrystallization. Further, in comparison of their total yield,(R)-(+)-1-phenylethylamine gives the product in 40% yield, and on theother hand, dibenzylamine does in 61% yield.

That is, though dibenzylamine is an optically inactive amine, it canwork to enhance the optical purity of (2R)-2-propyloctanoic acid, andthe effect of improving the optical purity is excellent in both of yieldand efficiency.

Thus, the process for increasing the optical purity of a material usingan optically inactive amine can be applied to large scale treatment andis convenient and inexpensive in comparison with the above process usingan optically active amine. Thus, this process is industrially excellent.

Application to Pharmaceuticals:

The crystals of the present invention, as they contain a crystalcomprising (2R)-2-propyloctanoic acid as an active ingredient and anamine, are useful in prevention, treatment and/or suppression of, forexample, neurodegenerative disease, neuropathy, or disease in need ofnerve regeneration, or their progress, in a mammal (for example, human,non-human animal, e.g., monkey, sheep, bovine, equine, dog, cat, rabbit,rat, mouse, etc.).

The term neurodegenerative disease includes all of diseases accompaniedby degeneration of nerve cell, and is not limited by its cause. Theneurodegenerative disease in the present invention also includesneuropathy or disease in need of nerve regeneration. The nerve cell maybe any type of nerve cells in the living body, including, for example,central nerves (e.g., cerebral nerves, spinal nerves, etc.), peripheralnerves (e.g., autonomic nervous system (e.g., sympathetic nerve,parasympathetic nerve, etc.), etc.) and so on. The neurodegenerativedisease is, for example, a disease of central nerve, includingParkinson's disease, Parkinson syndrome, Alzheimer's disease, Down'sdisease, amyotrophic lateral sclerosis, familial amyotrophic lateralsclerosis, progressive supranuclear palsy, Huntington's disease,spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy,olivopontocerebellar atrophy, cortical basal degeneration, familialdementia, frontal temporal dementia, senile dementia, diffuse Lewy bodydisease, striatonigral degeneration, chorea athetosis, dystonia, Meigs'ssyndrome, late cortical cerebellar atrophy, familial spastic paraplegia,motor neuron disease, Machado-Joseph disease, Pick's disease, nervousdysfunction after cerebral apoplexy (for example, brain hemorrhage(e.g., hypertensive intracerebral bleeding, etc.), cerebral infarction(e.g., cerebral thrombosis, cerebral embolus, etc.), transient ischemicattack, subarachnoid hemorrhage, etc.), nervous dysfunction after spinaldamage, demyelinating disease (for example, multiple sclerosis,Guillain-Barré syndrome, acute disseminated encephalomyelitis, acutecerebellitis, transverse myelitis, etc.), brain tumor (for example,astrocytoma, etc.), cerebrospinal disease caused by infection (forexample, meningitis, cerebral abscess, Creutzfeldt-Jakob disease, AIDSdementia, etc.), mental disease (schizophrenia, manic-depressivepsychosis, neurosis, psychosomatic disease, epilepsy, etc.) and thelike. The neurodegenerative disease is more preferably Parkinson'sdisease, Parkinson syndrome, Alzheimer's disease, amyotrophic lateralsclerosis, familial amyotrophic lateral sclerosis, or the like.

The neuropathy includes all of the nervous dysfunction. That is, theneuropathy generally includes disorders recognized as a symptom duringdisease. For example, Parkinson's disease or Parkinson syndrome isaccompanied by for example tremor, myospasm (rigidity), bradypragia,postural disturbance, dysautonomia, pulsion phenomenon, gait disorder,mental symptom, and so on. For example, Alzheimer disease is accompaniedby dementia symptom; the amyotrophic lateral sclerosis or familialamyotrophic lateral sclerosis is accompanied by muscle atrophy, muscleweakness, dysfunction of upper extremity, gait disorder, dysarthria,dysphagia, respiration disorder, and so on.

The disease in need of nerve regeneration is means those in which theabsolute number of the neurocytes are reduced by lack of neurocytes tospoil normal neural function, including, for example, the aboveneurodegenerative disease in such a state. In such a disease, a cellcapable of generating normal nerves (for example, nerve stem cell, nerveprecursor cell, nerve cell, other stem cell, glia cell, etc.) istransplanted surgically or an intrinsic cell of them is activated toregenerate the nerve for therapy. The crystal of the present inventionmay be administered temporarily or continuously at the time oftransplantation of the above cell or of activation of the intrinsic cellto accelerate nerve regeneration.

Further, the crystal of the present invention is also useful as a nerveregeneration accelerator or S100β-increase inhibitor. The crystal of thepresent invention may be formulated into the above pharmaceuticalpreparations for administration to the living body with the aim ofprevention, treatment and/or suppression of progress of theabove-mentioned diseases. In the present invention, the term“prevention” means to prevent the onset of disease itself; “treatment”means to lead the state of disease to cure; and “suppression ofprogress” means to suppress the deterioration or stop the progress ofthe state.

The dosage depends on age, body weight, condition, therapeutic effect,method of administration, time of treatment, and so on, though it may beadministered orally at a dose of 1 mg to 5000 mg for an adult once orseveral times a day, or parenterally (preferably intravenously) at adose of 1 mg to 1200 mg once or several times a day, or infusedintravenously continuously for 1 hour to 24 hours a day.

As mentioned above, however, the dosage is variable depending on variousconditions, and accordingly the dosage may be lower than or over theabove defined dosage in some cases.

In addition, naturally, (2R)-2-propyloctanoic acid with the opticalpurity over 99.5% e.e. in the present invention is effective inprevention, treatment and/or suppression of progress of the abovediseases. Such (2R)-2-propyloctanoic acid may be formulated into apharmaceutical preparation as mentioned above; as it has a property ofoil, it is preferably formulated into injection or filled in softcapsules, utilizing the characteristics of liquid. For example, in asoft capsule, the dosage may be the same as mentioned above, but a dailydosage is preferably about 50 to about 5000 mg, particularly about 100to about 1200 mg. The dosage as injection is variable depending on thedegree of symptom; age of the subject, gender, body weight; timing ofadministration, or intervals of administration, and there is noparticular limitation; for example, it may be in the same range asmentioned above, or it may be intravenously injected as infusion, forexample, as an agent for neurodegenerative disease such as cerebralinfaction at a daily dose of about 2 to about 12 mg per kg body weightof a patient. More preferably, it may be administered at a daily dose ofabout 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, or about 12mg per kg body weight of a patient. Even more preferably, it may beadministered at a daily dose of about 4 mg, about 6 mg, about 8 mg, orabout 10 mg per kg body weight of a patient. Particularly, the dailydose is about 4 mg or about 8 mg per kg body weight of a patient.

The pharmaceutical composition containing the crystal of the presentinvention or (2R)-2-propyloctanoic acid having an optical purity of morethan 99.5% e.e. as active ingredient may be also combined with, forexample, an anticonvulsant (e.g., phenobarbital, mephobarbital,metharbital, primidone, phenyloin, ethotoin, trimethadione,ethosuximide, acetylphenetride, carbamazepine, acetazolamide, diazepam,sodium valproate, etc.), an acetylcholinesterase inhibitor (e.g.,donepezil hydrochloride, TAK-147, rivastigmine, galantamine, etc.), aneurotrophic factor (e.g., ABS-205, etc.), an aldose reductaseinhibitor, an antithrombotic (e.g., t-PA, heparin), an oralanticoagulant (e.g., warfarin, etc.), a synthetic antithrombin drug(e.g., gabexate mesylate, nafamostat mesylate, argatroban, etc.), anantiplatelet drug (e.g., aspirin, dipyridamole, ticlopidinehydrochloride, beraprost sodium, cilostazol, sodium ozagrel, etc.), athrombolytic agent (e.g., urokinase, tisokinase, alteprase, etc.), aFactor Xa inhibitor, a Factor VIIa inhibitor, a cerebral blood flow andmetabolism improver (e.g., idebenone, calcium hopantenate, amantadinehydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate,pyrithioxin hydrochloride, γ-aminobutyric acid, bifemelanehydrochloride, lisuride maleate, indeloxazine hydrochloride,nicergoline, propentofylline, etc.), in antioxidant (e.g., edaravone,etc.), a glycerin preparation (e.g., glyceol, etc.), a β-secretaseinhibitor (e.g.,6-(4-biphenyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline,6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetraline,6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetraline,2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetraline,6-(4-biphenyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetraline,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetraline,242-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetraline,6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline,6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline,6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline,and optical isomers, salts and hydrates thereof, OM99-2 (WO 01/00663),etc.), β-amyloid protein aggregation inhibitor (e.g., PTI-00703,ALZHEMED (NC-531), PPI-368 (JP-T-11-514333), PPI-558 (JP-T-2001-500852),SKF-74652 (Biochem. J., 340(1), 283-289 (1999)), etc.), a cerebralfunction activator (e.g., aniracetam, nicergoline, etc.), a dopaminereceptor agonist (e.g., L-dopa, bromocriptine, pergolide, talipexole,pramipexole, cabergoline, amantadine, etc.), a monoamine oxidase (MAO)inhibitor (e.g., safrazine, deprenyl, selegiline, ramacemide, riluzole,etc.), an anticholinergic drug (e.g., trihexyphenidyl, biperiden, etc.),a COMT inhibitor (e.g., entacapone, etc.), a therapeutic agent foramyotrophic lateral sclerosis (e.g., riluzole, a neurotrophic factor,etc.), a statin-based therapeutic agent for hyperlipidemia (e.g., sodiumpravastatin, atorvastatin, simvastatin, rosuvastatin, etc.), afibrate-based therapeutic agent for hyperlipidemia (e.g., clofibrate,etc.), an apoptosis inhibitor (e.g., CPI-1189, IDN-6556, CEP-1347,etc.), a nerve differentiation and regeneration promoter (e.g.,leteprinim, xaliproden (SR-57746-A), SB-216763, etc.), a non-steroidalanti-inflammatory drug (e.g., meloxicam, tenoxicam, indomethacin,ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), a steroiddrug (e.g., dexamethasone, hexestrol, cortisone acetate, etc.), a sexualhormone or derivatives thereof (e.g., progesterone, estradiol, estradiolbenzoate, etc.), or the like. Furthermore, it may be also combined witha nicotinic receptor regulator, a γ-secretase inhibitor, a β-amyloidvaccine, a β-amyloid protease, a squalene synthetase inhibiting agent, atherapeutic agent for the abnormal behavior, wandering or the likeassociated with progress of dementia, a hypotensor, a therapeutic agentfor diabetes mellitus, an antidepressant, an antianxiety agent, adisease-modifying antirheumatoid agent, an anticytokine agent (e.g., aTNF inhibitor, a MAP kinase inhibitor, etc.), a parathyroid hormone(PTH), a calcium receptor antagonist or the like.

These combination medicaments are only exemplary and are not limited tothese.

Other medicaments may be administered in any combination of two or more.Furthermore, the medicaments for combined use include those that havebeen discovered as well as those that are to be discovered afterward,based on the mechanism described above.

Pharmacological Activity:

It can be confirmed by a known method, for example, a method describedin the specification of EP Patent 0632008, EP-A-1174131 or the like thatthe crystal of the present invention has high pharmacological activitysimilar to (2R)-2-propyloctanoic acid.

Toxicity:

Toxicity of (2R)-2-propyloctanoic acid or a salt thereof is very low,and it is considered to be sufficiently safe for the use as apharmaceutical drug.

EFFECT OF THE INVENTION

According to the present invention, crystals comprising(2R)-2-propyloctanoic acid and an amine, which can be used as bulk drugsfor safely orally administrable solid preparations with keeping thepharmacological effect, are provided. Among these crystals, the crystalwith dibenzylamine per se is particularly useful not only as bulk drugfor pharmaceuticals but also as an intermediate to produce(2R)-2-propyloctanoic acid having a remarkably high optical purity ofmore than 99.5% e.e.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be explained in detail by way ofExamples, which are not intended as a limitation thereof. They may bechanged within the scope of the present invention as far as they do notdeparture from the scope of the present invention.

Reference Example 1 (1S)-1-Propylheptyl 4-methylbenzenesulfonate

Under an argon atmosphere, cuprous chloride (4.6 g) was added to asolution of (2R)-2-hexyloxirane (300 g) in tetrahydrofuran (642 mL), andthen ethylmagnesium chloride tetrahydrofuran solution (2.1 mol/L, 1309g) was added dropwise at −40 to −20° C. (inner temperature). Thereaction mixture was stirred at −30 to −20° C. (inner temperature) forabout 30 minutes, and then tosyl chloride (491 g) was added, and themixture was stirred at 0-20° C. (inner temperature) for about 4 hours.To the reaction mixture was then added 10 v/v % sulfuric acid (conc.sulfuric acid:water=65 mL:650 mL), aqueous sodium chloride (13.6 g)solution (272 mL) and ethyl acetate (1.5 L) for extraction. Theresulting organic layer was washed with (1) a solution of sodiumchloride (32 g) in water (636 mL), (2) a mixture of a solution ofpotassium carbonate (73 g) in water (730 mg) and a saturated brine (200mL), and (3) a saturated brine (600 mL) in order, and then concentratedto give the title compound (758.7 g; yield 89%).

TLC: Rf 0.44 (hexane:ethyl acetate=10:1);

NMR (CDCl₃): δ 0.83 (t, J=7.3 Hz, 3H), 0.85 (t, J=7.1 Hz, 3H), 1.24 (m,10H), 1.56 (m, 4H), 2.44 (s, 3H), 4.56 (m, 1H), 7.32 (d, J=8.1 Hz, 2H),7.79 (d, J=8.1 Hz, 2H).

Reference Example 2 (2R)-2-propyloctanenitrile

Under an argon atmosphere, 1,3-dimethyl-2-imidazolidinone (624 mL) andacetone cyanohydrin (394 g) were added to a solution of the compound(758.7 g) produced in Reference Example 1 in tetrahydrofuran (1458 mL),and additionally lithium hydroxide (96.8 g) was added at roomtemperature, and the mixture was stirred at 50-55° C. (innertemperature) for about 14 hours. A solution of sodium chloride (400 g)in water (2.2 L) was added to the reaction mixture and extracted with amixture of n-hexane and ethyl acetate (2:1) (1660 mL). The resultingorganic layer was washed with a solution of sodium chloride (150 g) inwater (830 mL) and concentrated. The residue was purified bydistillation to give the title compound having the followingphysicochemical properties (335 g [92.1 area %], 97.1% e.e.; 89% yield).

The optical purity of the title compound was determined by gaschromatography.

TLC: Rf 0.54 (hexane:ethyl acetate=10:1);

NMR (CDCl₃): δ 0.89 (t, J=6.59 Hz, 3H), 0.95 (t, J=7.05 Hz, 3H), 1.46(m, 14H), 2.52 (m,

Reference Example 3 (2R)-2-propyloctanamide

Under an argon atmosphere, dimethylsulfoxide (177 g) and potassiumcarbonate (16.5 g) were added to a solution of the compound (122 g [82.0area %], 96.2% e.e.) produced in the same manner as in Reference Example2, and 35% hydrogen peroxide (8.7 g) was added dropwise thereto at50-70° C. (inner temperature), followed by stirring for about 1 hour. Asolution of sulfurous acid (9.3 g) in water (720 mL) was added to thereaction mixture, cooled to about 10° C. (inner temperature) and stirredfor 30 minutes. The reaction mixture was filtered, washed with anacetonitrile:water (1:2) mixture (435 mL) and with water (632 mL) togive crude crystals of the title compound (133 g [84.3 area %], 96.5%e.e., moisture content 15 w/w %). To the crude crystals (40 g) was addedacetonitrile (240 mL) and water (160 mL), and the mixture was warmed upat 56-60° C. (inner temperature) to dissolve the crude crystals. Thesolution was cooled down to about 29° C. (inner temperature) at acooling rate of 10-15° C./60 minutes, and after addition of water (80mL) down to 15° C.-16° C. at a cooling rate of 10-15° C./60 minutes. Thereaction mixture was stirred at this temperature for about 30 minutes,filtered, and washed with a acetonitril:water (1:2) mixture (80 mL) togive the crystals of the title compound having the followingphysicochemical properties (30.8 g [97.8 area %], 99.7% e.e., moisturecontent 11.6 w/w %).

The optical purity of the title compound was determined by liquidchromatography.

TLC: Rf 0.24 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 0.89 (m, 6H), 1.34 (m, 12H), 1.58 (m, 2H), 2.11 (m, 1H),5.40 (brs., 1H), 5.51 (brs., 1H);

IR (KBr method): 3373, 3181, 2954, 2928, 2871, 2851, 1657, 1465, 1452,1424, 1377, 1319, 1298, 1285, 1242, 1230, 1214, 1192, 1148, 1136, 1106,987, 899, 830, 784, 762, 743, 729, 683, 627 cm⁻¹.

Reference Example 4 (2R)-2-propyloctanoic acid

Under an argon atmosphere, the compound (100 g) produced in ReferenceExample 3 was dissolved in acetic acid (230 mL) at about 40° C. (innertemperature). A solution of methanesulfonic acid (130 g) in water (182mL) was added to the above solution, then stirred at about 105-112° C.(inner temperature) for about 13 hours, and cooled to about 28° C.(inner temperature). Then, water (400 mL) and a mixture of n-heptane:isopropyl acetate (5:1) (500 mL) were added and the mixture wasextracted. The organic layer was washed twice with water (400 mL) andconcentrated to give (2R)-2-propyloctanoic acid having the followingphysicochemical properties (103 g, 99.3% e.e.).

The optical purity was determined by liquid chromatography afterconversion into the phenacyl ester.

TLC: Rf 0.54 (hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 0.86-0.93 (m, 6H), 1.25-1.50 (m, 2H), 2.36 (m, 1H).

Example 1 Crystal comprising (2R)-2-propyloctanoic acid anddibenzylamine

To (2R)-2-propyloctanoic acid (103 g) produced in Reference Example 4was added acetonitrile (1.5 L) and dibenzylamine (58.6 g), and themixture was stirred at about 60° C. (inner temperature) for 10-25minutes, then cooled to 10-20° C. (inner temperature) at a cooling rateof 10° C./60 minutes, then stirred for about 30 minutes, and filtered.The resulting crystals were washed with acetonitrile (200 mL) and driedin vacuo at about 40° C. to give the compound of the present inventionhaving the following physicochemical properties (136 g, 99.8% e.e.;yield 88%). The resulting compound of the present invention wascrystals.

The optical purity of the compound of the present invention wasdetermined by liquid chromatography as a phenacyl ester derived from thecompound of the present invention through the free form according to themethod as shown in Example 2 below.

NMR (CDCl₃): δ 0.87 (t, J=6.78 Hz, 6H), 0.91 (t, J=7.23 Hz, 6H), 1.35(m, 24H), 1.60 (m, 4H), 2.33 (tt, J=8.79, 5.22 Hz, 2H), 3.87 (s, 4H),7.30 (m, 10H);

Melting point: 79.5-79.7° C.

Physicochemical Data of the Crystal:

For the compound produced in Example 1, a chart of powdered X-raydiffraction spectrum is shown in FIG. 1, a chart of infrared absorptionspectrum (IR) in FIG. 2, and a chart of differential scanningcalorimetry (DSC) in FIG. 3, respectively. In addition, the results ofelemental analysis and specific rotation are described.

[1] Powdered X-Ray Diffraction Spectrum <Measurement Conditions>

Apparatus: BRUKER axs, BRUKER D8 DISCOVER with GADD(C2) Target: CuFilter: none Voltage: 40 kV Current: 40 mA Time of Exposure: 5 min

<Results>

FIG. 26 shows the results.

TABLE 26 Crystal with dibenzylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 15.27 5.80 64.9 17.03 5.20 34.519.04 4.66 100.0 19.99 4.44 85.7 21.36 4.16 25.8 22.91 3.88 80.4 24.213.67 89.1 26.09 3.41 30.7 26.70 3.34 28.9 28.42 3.14 23.8 30.83 2.9024.6 34.06 2.63 22.3

[2] Infrared Absorption (IR) Spectrum <Measurement Conditions>

Apparatus: JASCO Corporation, FTIR-660Plus/Sens IR TECHNOLOGIES,DuraScope Method of Measurement: measured by a KBr method Resolution: 4cm⁻¹ Frequency of scanning: 16 times

<Results>

IR (KBr method): 3434, 3068, 3036, 2957, 2926, 2872, 2853, 2756, 2621,2454, 1948, 1638, 1498, 1466, 1457, 1415, 1379, 1342, 1321, 1212, 1141,1112, 1096, 1044, 989, 936, 905, 812, 763, 744, 694 cm⁻¹.

[3] Differential Scanning Calorimetry (DSC)< <Measurement Conditions>

Apparatus: METTLER TOLEDO, DSC822e Amount of Sample: 1.15 mg SampleCell: Aluminum open cell Flow Rate of Argon Gas: 40 mL/min ProgrammingRate: 5° C./min

<Results>

Endothermic peak was found at approximately 81.8° C.

[4] Elemental Analysis <Results>

Anal. Calcd for C₃₆H₅₉N: C, 75.88; H, 10.44; N, 2.46;

Found: C, 75.78; H, 10.25, N, 2.50.

[5] Specific Optical Rotation <Results>

[α]_(D) ²⁰=−3.6° (c=2.00, ethanol).

Example 2 (2R)-2-propyloctanoic acid

Under an argon atmosphere, aqueous 1N-potassium hydroxide solution (400mL) was added to the compound (100 g) produced in Example 1 at about 20°C. (inner temperature), and the mixture was stirred for about 10minutes. This solution was back-extracted with isopropyl acetate (250mL×2). The resulting aqueous layer was extracted with addition of amixture of n-heptane: isopropyl acetate (1:1) (500 mL) and conc.hydrochloric acid (40 mL). The resulting organic layer was washed withwater (200 mL) and saturated brine (200 mL) in order and concentrated.The resulting residue was purified by distillation to give the compoundof the present invention having the following physicochemical properties(63.5 g [100 area %], 99.8% e.e.; yield 97%).

The optical purity was determined by liquid chromatography afterconversion into the phenacyl ester.

TLC: Rf 0.54 (hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 0.86-0.93 (m, 6H), 1.25-1.50 (m, 2H), 2.36 (m, 1H);

IR (liquid film method): 2958, 2930, 2859, 2360, 1706, 1466, 1417, 1381,1289, 1254, 1216, 1110, 943, 565 cm⁻¹.

In this connection, in (2R)-2-propyloctanoic acid obtained from(2R)-2-propyloctanoic acid of optical purity 99.0% e.e. through the sameoperation as that from Example 1 to Example 2, the optical purity was99.6% e.e., and the specific rotation was [α]_(D) ²⁰=−6.2° (c=2.0;ethanol).

Example 3 Crystal comprising (2R)-2-propyloctanoic acid anddibenzylamine

Using a variety of solvent in place of acetonitrile, the same operationas in Example 1 was repeated to elucidate the yield of the titlecrystal. In addition, using those crystals, the same operation as inExample 2 was repeated to elucidate the optical purity of the resulting(2R)-2-propyloctanoic acid.

The following table shows the solvent used, the amount of the solventused, yield and optical purity. The amount of the solvent used wasrepresented by a volume ratio for the total weight of solute. In thisexamination, (2R)-2-propyloctanoic acid used as a starting material had99.2% e.e. of optical purity.

TABLE 27 Optical Solvent Solvent amount Yield purity acetonitrile 10 95%99.6% e.e. acetonitrile 15 100% 99.6% e.e. acetonitrile 20 95% 99.7%e.e. acetonitrile 25 71% 99.7% e.e. acetonitrile:isopropyl alcohol =50:1 15 85% 99.7% e.e. acetonitrile:water = 50:1 15 79% 99.7% e.e.dimethyl carbonate 34% 99.8% e.e. isopropyl alcohol:water = 1:1 10 71%99.7% e.e. isopropyl alcohol:water = 1.5:1 10 50% 99.7% e.e. isopropylalcohol:water = 1.2:1 10 54% 99.8% e.e. isopropyl alcohol:water = 1:1.210 83% 99.6% e.e. isopropyl alcohol:water = 1:1.5 10 96% 99.5% e.e.isopropyl alcohol:water = 1:2 10 100% 99.4% e.e. isopropyl alcohol:water= 5.1:3.5 8.6 41% 99.8% e.e. methanol:water = 5.5:2.5 8 41% 99.8% e.e.ethanol:water = 5.3:3.5 8.8 46% 99.8% e.e. dimethoxyethane:water = 5:3 8100% 99.3% e.e.

<Results>

It was found that the use of the crystal comprising(2R)-2-propyloctanoic acid and dibenzylamine as an intermediate forproducing optically highly pure (2R)-2-propyloctanoic acid gives(2R)-2-propyloctanoic acid having the optical purity of over 99.5% e.e.,efficiently.

Examples 4(1)-4(27)

Using a variety of amines in place of dibenzylamine, the same operationas in Example 1 was repeated to give compounds having the followingphysicochemical properties. The resulting compounds of the presentinvention were crystals. In this example, the experiment was carried outin the presence or absence of a variety of solvents. The solvents usedin crystallization are respectively described in each item (when nosolvent was used, no solvent is indicated). The optical purity of(2R)-2-propyloctanoic acid used as a starting material in thisexperiment, was 95.0% e.e. in Examples 4(1)-4(16), 99.2% e.e. inExamples 4(17)-4(20), and 99.4% e.e. in Examples 4(21)-4(27).

Physicochemical data of the crystal:

For the compound produced in Example 4(1)-4(27), charts of powderedX-ray diffraction spectrum and charts of infrared absorption spectrum(IR) are shown in Figs. below. The condition of measurement was asfollows.

[1] Powdered X-Ray Diffraction Spectrum <Measurement Conditions>

Apparatus: BRUKER axs, BRUKER D8 DISCOVER with GADD(C2) Target: CuFilter: none Voltage: 40 kV Current: 40 mA Time of Exposure: 5 min

[2] Infrared Absorption (IR) Spectrum <Measurement Conditions>

Apparatus: JASCO Corporation, FTIR-660Plus/Sens IR TECHNOLOGIES,DuraScope Method of Measurement: measured by an ATR method Resolution: 4cm⁻¹ Frequency of scanning: 16 times

Example 4(1) Crystal comprising (2R)-2-propyloctanoic acid and(+)-dehydroabietylamine

NMR (CDCl₃): δ 7.15 (1H, d, J=8.0 Hz), 6.98 (1H, d, J=9.6 Hz), 6.88 (1H,brs), 2.91-2.77 (3H, m), 2.60 (2H, brs), 2.27 (2H, m), 1.78-1.20 (31H,m), 0.94-0.84 (9H, m);

Melting point: 118.4-122.0° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 28 Crystal with (+)-dehydroabietylamine Diffraction angle (2θ)Half width Relative intensity (degree) (Å) (%) 12.16 7.27 15.2 12.906.86 14.2 14.04 6.30 17.1 15.15 5.84 88.6 15.70 5.64 40.2 16.46 5.3832.4 17.08 5.19 63.7 18.35 4.83 100.0 18.96 4.68 44.3 19.45 4.56 44.220.56 4.32 67.1 22.31 3.98 26.9 23.35 3.81 25.5 24.44 3.64 37.5 25.653.47 24.8IR (ATR method): 2954, 2925, 2850, 2663, 2197, 1560, 1534, 1497, 1456,1436, 1394, 1360, 1298, 1210, 1173, 1147, 1109, 1056, 1005, 911, 883,854, 822, 777, 752, 726, 674, 630 cm⁻¹;Solvent: a mixed solvent of methanol and water, a mixed solvent ofethanol and water, isopropyl alcohol, acetone, acetonitrile,dimethoxyethane, ethyl acetate, diethyl carbonate, toluene, methylt-butyl ether, n-hexane, diethyleneglycol dimethyl ether.

Example 4(2) Crystal comprising (2R)-2-propyloctanoic acid and(R)-(−)-2-phenylglycinol

NMR (CDCl₃): δ 7.38-7.28 (5H, m), 4.15 (1H, dd, 7=4.4, 8.8 Hz), 3.78(1H, dd, J=4.4, 11.6 Hz), 3.67 (1H, dd, J=8.8, 11.6 Hz), 2.28 (1H, m),1.62-1.23 (14H, m), 0.89 (3H, t, J=7.2 Hz), 0.87 (3H, t, J=6.8 Hz);

Melting point: 82.8-83.6° C.;

IR (ATR method): 3034, 2953, 2926, 2854, 2668, 2509, 2143, 1640, 1605,1522, 1457, 1400, 1376, 1339, 1316, 1281, 1228, 1207, 1186, 1119, 1065,1049, 994, 919, 891, 854, 787, 758, 700, 537 cm⁻¹;

Solvent: isopropyl alcohol, acetonitrile, ethyl acetate, diethylcarbonate, toluene, methyl t-butyl ether, n-hexane, diethyleneglycoldimethyl ether.

Example 4(3) Crystal comprising (2R)-2-propyloctanoic acid and(S)-(+)-2-phenylglycinol

NMR (CDCl₃): δ 7.38-7.22 (5H, m), 4.15 (1H, dd, J=4.0, 8.4 Hz), 3.78(1H, dd, J=4.0, 11.2 Hz), 3.66 (1H, dd, J=8.4, 11.2 Hz), 2.28 (1H, m),1.62-1.19 (14H, m), 0.90 (3H, t, J=7.2), 0.87 (3H, t, J=7.2);

Melting point: 86.1-86.7° C.;

IR (ATR method): 3033, 2953, 2925, 2870, 2850, 2670, 2516, 2155, 1641,1567, 1524, 1496, 1457, 1433, 1393, 1308, 1208, 1182, 1149, 1112, 1067,1054, 1030, 1000, 920, 893, 860, 801, 758, 701 cm⁻¹;

Solvent: acetonitrile, ethyl acetate, diethyl carbonate, methyl t-butylether, n-hexane.

Example 4(4) Crystal comprising (2R)-2-propyloctanoic acid and(−)-cis-myrtanylamine

NMR (CDCl₃): δ 2.77 (211, d, J=7.2 Hz), 2.36 (1H, m), 2.21 (2H, m),2.04-1.85 (5H, m), 1.59-1.21 (16H, m), 0.97 (3H, s), 0.93-0.86 (9H, m);

Melting point: 70.3-73.2° C.;

Powder X-ray diffraction spectral data:

TABLE 29 Crystal with (−)-cis-myrtanylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 11.23 7.88 6.3 14.53 6.09 19.615.43 5.74 21.4 16.55 5.35 87.6 17.74 5.00 100.0 18.71 4.74 56.0 19.574.53 56.4 21.44 4.14 45.9 22.45 3.96 22.2 23.29 3.82 11.2 24.45 3.6416.1 25.60 3.48 18.7 26.57 3.35 14.1 27.20 3.28 16.4 27.50 3.24 16.029.74 3.00 13.6 31.20 2.86 16.1 32.92 2.72 12.6 34.22 2.62 12.1 35.792.51 8.7 36.59 2.45 9.7

IR (ATR method): 2989, 2952, 2919, 2869, 2852, 2611, 2196, 1626, 1517,1458, 1397, 1363, 1320, 1230, 1214, 1139, 1116, 1035, 1005, 978, 919,874, 848, 809, 779, 747, 721, 637 cm⁻¹;

Solvent: acetonitrile, ethyl acetate, diethyl carbonate, toluene, methylt-butyl ether, n-hexane.

Example 4(5) Crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(p-tolyl)ethylamine

NMR (CDCl₃): δ 7.26-7.13 (4H, m), 4.14 (1H, q, J=6.4 Hz), 2.33 (3H, s),2.26 (1H, m), 1.61-1.20 (17H, m), 0.91-0.85 (6H, m);

Melting point: 86.3-87.3° C.;

Powder X-ray diffraction spectral data:

TABLE 30 Crystal with (R)-(+)-1-(p-tolyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 11.34 7.79 24.412.01 7.36 8.7 12.81 6.91 31.7 13.69 6.46 6.7 15.08 5.87 8.8 16.15 5.4845.5 17.47 5.07 20.9 18.84 4.71 100.0 20.08 4.42 28.2 20.68 4.29 71.722.03 4.03 19.3 23.00 3.86 89.2 24.14 3.68 27.1 25.65 3.47 54.2 27.413.25 29.2 28.22 3.16 17.1 29.92 2.98 14.6 30.99 2.88 14.0 32.64 2.7415.6 33.22 2.70 14.6 34.46 2.60 12.3

IR (ATR method): 2954, 2925, 2856, 2702, 2536, 2210, 1621, 1567, 1518,1464, 1440, 1405, 1381, 1315, 1306, 1231, 1172, 1111, 1090, 1021, 993,898, 868, 849, 813, 779, 744, 722, 685 cm⁻¹;

Solvent: a mixed solvent of methanol and water, a mixed solvent ofacetone and water, acetonitrile, dimethoxyethane, ethyl acetate, diethylcarbonate, n-hexane.

Example 4(6) Crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(1-naphthyl)ethylamine

NMR (CDCl₃): δ 8.10 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.4 Hz), 7.77 (1H,d, J=8.4 Hz), 7.63 (1H, d, J=6.8 Hz), 7.56-7.46 (3H, m), 5.04 (1H, q,J=6.8 Hz), 2.29 (1H, m), 1.60 (3H, d, J=6.8 Hz), 1.61-1.26 (14H, m),0.91-0.85 (6H, m);

Melting point: 73.4-76.7° C.;

Powder X-ray diffraction spectral data:

TABLE 31 Crystal with (R)-(+)-1-(1-naphthyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 10.97 8.06 14.413.38 6.61 58.1 15.84 5.59 48.9 16.91 5.24 31.0 17.67 5.02 40.8 19.314.59 54.2 20.46 4.34 34.3 21.52 4.13 43.2 22.21 4.00 100.0 23.49 3.7867.5 24.41 3.64 24.2 25.11 3.54 24.1 26.78 3.33 22.7 28.12 3.17 14.728.96 3.08 21.3 31.28 2.86 20.6 33.79 2.65 13.8 35.87 2.50 12.9 36.772.44 12.4

IR (ATR method): 2952, 2924, 2854, 2759, 2582, 2180, 1629, 1571, 1509,1467, 1454, 1433, 1402, 1389, 1378, 1335, 1305, 1275, 1253, 1231, 1173,1110, 1076, 1004, 950, 900, 860, 801, 774 cm⁻¹;

Solvent: acetonitrile, n-hexane.

Example 4(7) Crystal comprising (2R)-2-propyloctanoic acid and(S)-(−)-1-(1-naphthyl)ethylamine

NMR (CDCl₃): δ 8.12 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.4 Hz), 7.76 (1H,d, J=8.4 Hz), 7.63 (1H, d, J=7.2 Hz), 7.56-7.46 (3H, m), 5.02 (1H, q,J=6.8 Hz), 2.32 (1H, m), 1.64-1.21 (17H, m), 0.92-0.85 (6H, m);

Melting point: 74.4-75.5° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 32 Crystal with (S)-(−)-1-(1-naphthyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 12.41 7.13 22.813.71 6.45 24.6 14.05 6.30 20.6 15.12 5.86 41.4 16.27 5.45 35.1 16.805.27 54.0 17.57 5.04 57.3 18.72 4.74 53.3 19.35 4.58 94.0 19.96 4.4557.4 21.00 4.23 74.1 21.50 4.13 57.6 22.41 3.96 100.0 23.56 3.77 27.523.95 3.71 28.0 25.55 3.48 49.7 26.21 3.40 41.1 27.79 3.21 32.9 28.563.12 25.9 30.92 2.89 26.0

IR (ATR method): 2952, 2922, 2850, 2219, 1624, 1601, 1557, 1514, 1467,1454, 1395, 1377, 1317, 1279, 1223, 1177, 1108, 1075, 1030, 1002, 950,923, 898, 860, 849, 799, 775, 749 cm⁻¹;

Solvent: acetonitrile, n-hexane.

Example 4(8) Crystal comprising (2R)-2-propyloctanoic acid andL-tyrosinamide

NMR (CDCl₃): δ 7.07 (2H, d, J=8.4 Hz), 6.74 (2H, d, J=8.4 Hz), 3.70 (1H,dd, J=6.0, 8.0 Hz), 3.00 (1H, dd, J=6.0, 13.6 Hz), 2.80 (1H, dd, J=8.0,13.6 Hz), 2.22 (1H, m), 1.59-1.22 (14H, m), 0.92-0.86 (6H, m);

Melting point: 109.3-111.1° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 33 Crystal with L-tyrosinamide Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 12.10 7.31 10.7 12.83 6.89 8.7 14.676.03 15.3 15.44 5.73 17.4 16.46 5.38 57.5 17.08 5.19 100.0 18.19 4.8740.7 19.89 4.46 91.5 21.30 4.17 66.1 22.12 4.02 40.1 23.31 3.81 61.624.15 3.68 48.1 25.81 3.45 37.5 27.36 3.26 43.0 28.66 3.11 20.8 29.852.99 19.7 30.95 2.89 23.2 32.97 2.71 29.2 33.48 2.67 21.9 35.00 2.5617.7 36.64 2.45 20.7

IR (ATR method): 3430, 2953, 2923, 2856, 1673, 1559, 1512, 1449, 1407,1376, 1349, 1324, 1266, 1242, 1210, 1175, 1108, 1078, 1037, 997, 850,830, 785, 736, 645 cm⁻¹;

Solvent: acetonitrile.

Example 4(9) Crystal comprising (2R)-2-propyloctanoic acid and(1S,2R)-(+)-2-amino-1,2-diphenylethanol

NMR (CDCl₃): δ 7.32-7.18 (10H, m), 4.85 (1H, d, J=6.0 Hz), 4.20 (1H, d,J=6.0 Hz), 2.34 (1H, m), 1.66-1.22 (14H, m), 0.91 (3H, t, J=7.2 Hz),0.88 (3H, t, J=6.8 Hz);

Melting point: 109.5-111.7° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 34 Crystal with (1S,2R)-(+)-2-amino-1,2-diphenylethanolDiffraction angle (2θ) Half width Relative intensity (degree) (Å) (%)13.60 6.51 25.5 14.18 6.24 20.4 15.96 5.55 100.0 17.33 5.11 44.1 18.354.83 22.5 19.47 4.56 62.7 20.46 4.34 82.6 21.41 4.15 59.3 22.45 3.9637.5 23.55 3.77 64.9 24.78 3.59 61.9 25.97 3.43 25.8 27.53 3.24 22.828.63 3.12 19.6 29.79 3.00 24.1 32.31 2.77 16.5 33.54 2.67 20.2 35.512.53 21.9

IR (ATR method): 2925, 2851, 1617, 1559, 1507, 1455, 1406, 1320, 1272,1204, 1134, 1081, 1047, 1007, 919, 848, 782, 765, 742, 699, 567 cm⁻¹;

Solvent: a mixed solvent of methanol and water, a mixed solvent ofethanol and water, isopropyl alcohol, a mixed solvent of acetone andwater, acetonitrile, dimethoxyethane, ethyl acetate, diethyl carbonate,toluene.

Example 4(10) Crystal comprising (2R)-2-propyloctanoic acid and(1R,2S)-(−)-2-amino-1,2-diphenylethanol

NMR (CDCl₃): δ 7.32-7.18 (10H, m), 4.84 (1H, d, J=6.0 Hz), 4.19 (1H, d,J=6.0 Hz), 2.33 (1H, m), 1.65-1.22 (14H, m), 0.91 (3H, t, J=7.2 Hz),0.88 (3H, t, J=7.2 Hz);

Melting point: 110.8-112.8° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 35 Crystal with (1R,2S)-(−)-2-amino-1,2-diphenylethanolDiffraction angle (2θ) Half width Relative intensity (degree) (Å) (%)10.06 8.79 8.9 11.94 7.41 21.5 12.88 6.87 8.8 15.11 5.86 37.0 15.97 5.5473.4 16.52 5.36 44.3 17.91 4.95 89.4 19.15 4.63 55.9 19.77 4.49 80.021.29 4.17 83.6 23.04 3.86 100.0 24.07 3.69 36.8 25.40 3.50 59.4 25.763.46 58.2 28.44 3.14 27.0 29.57 3.02 23.2 30.70 2.91 27.4 35.72 2.5126.0

IR (ATR method): 3275, 2953, 2925, 2856, 2605, 1617, 1560, 1542, 1508,1455, 1408, 1307, 1277, 1239, 1205, 1132, 1110, 1081, 1046, 1006, 921,907, 849, 811, 783, 765, 742, 700 cm⁻¹;

Solvent: a mixed solvent of methanol and water, a mixed solvent ofethanol and water, isopropyl alcohol, a mixed solvent of acetone andwater, acetonitrile, dimethoxyethane, ethyl acetate, diethyl carbonate,toluene.

Example 4(11) Crystal comprising (2R)-2-propyloctanoic acid and(+)-cis-2-benzylaminocyclohexanemethanol

NMR (CDCl₃): δ 7.37-7.27 (5H, m), 4.05-3.90 (3H, m), 3.69 (1H, dd,J=3.2, 11.2 Hz), 3.05 (1H, m), 2.26 (1H, m), 2.22 (1H, m), 2.16 (1H, m),1.87 (1H, m), 1.68-1.21 (21H, m), 0.90 (3H, t, J=7.2 Hz), 0.87 (3H, t,J=6.8 Hz);

Melting point: 64.6-67.0° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 36 Crystal with (+)-cis-2-benzylaminocyclohexanemethanolDiffraction angle (2θ) Half width Relative intensity (degree) (Å) (%)10.49 8.43 6.5 12.01 7.36 9.8 13.37 6.62 5.2 15.92 5.56 14.1 16.68 5.3118.7 17.90 4.95 100.0 19.83 4.47 28.8 21.16 4.20 34.2 22.75 3.91 13.924.34 3.65 9.4 26.06 3.42 12.5 27.68 3.22 13.5 28.56 3.12 10.8 30.372.94 9.9 32.05 2.79 11.1

IR (ATR method): 3034, 2951, 2926, 2853, 1622, 1526, 1498, 1450, 1406,1341, 1310, 1261, 1218, 1141, 1117, 1087, 1063, 1051, 1034, 1013, 974,914, 862, 841, 812, 785, 750, 696, 645 cm⁻¹;

Solvent: a mixed solvent of acetone and water, acetonitrile, n-hexane.

Example 4(12) Crystal comprising (2R)-2-propyloctanoic acid and(+cis-2-benzylaminocyclohexanemethanol

NMR (CDCl₃): δ 7.37-7.29 (5H, m), 4.05-3.90 (3H, m), 3.70 (1H, dd,J=3.2, 11.2 Hz), 3.05 (1H, m), 2.26 (1H, m), 2.14 (1H, m), 2.14 (1H, m),1.87 (1H, m), 1.68-1.23 (21H, m), 0.91-0.85 (6H, m);

Melting point: 71.6-73.1° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 37 Crystal with (−)-cis-2-benzylaminocyclohexanemethanolDiffraction angle (2θ) Half width Relative intensity (degree) (Å) (%)10.01 8.83 6.9 12.38 7.15 28.3 15.35 5.77 24.7 16.29 5.44 27.7 17.994.93 100.0 19.02 4.66 39.6 20.00 4.44 68.1 21.52 4.13 23.5 21.85 4.0628.8 22.84 3.89 24.8 23.93 3.71 15.3 24.87 3.58 21.4 25.46 3.50 27.228.03 3.18 21.2 29.91 2.99 17.5 31.21 2.86 16.7 35.00 2.56 11.3 35.892.50 13.1

IR (ATR method): 3033, 2949, 2925, 2854, 1622, 1524, 1497, 1454, 1397,1341, 1324, 1261, 1219, 1115, 1087, 1075, 1061, 1037, 1010, 975, 914,781, 750, 697, 634 cm⁻¹;

Solvent: a mixed solvent of methanol and water, a mixed solvent ofethanol and water, a mixed solvent of isopropyl alcohol and water,acetone, acetonitrile, a mixed solvent of dimethoxyethane and water,ethyl acetate, diethyl carbonate, methyl t-butyl ether, n-hexane.

Example 4(13) Crystal comprising (2R)-2-propyloctanoic acid and(S)-(−)-2-amino-3-phenyl-1-propanol

NMR (CDCl₃): δ 7.33-7.13 (5H, m), 3.72 (1H, dd, J=4.0, 11.6 Hz), 3.49(1H, dd, J=7.2, 11.6 Hz), 3.22 (1H, m), 2.84 (1H, dd, J=5.6, 13.6 Hz),2.65 (1H, dd, J=8.8, 13.6 Hz), 2.28 (1H, m), 1.62-1.18 (14H, m), 0.90(3H, t, J=7.6 Hz), 0.86 (3H, t, J=7.6 Hz);

Melting point: 67.4-69.7° C.;

IR (ATR method): 3241, 3029, 2953, 2925, 2853, 2546, 2163, 1623, 1576,1541, 1497, 1456, 1398, 1374, 1338, 1285, 1206, 1175, 1113, 1093, 1065,1031, 997, 944, 915, 850, 806, 740, 697 cm⁻¹;

Solvent: acetonitrile, ethyl acetate, diethyl carbonate, n-hexane.

Example 4(14) Crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-2-amino-3-phenyl-1-propanol

NMR (CDCl₃): δ 7.33-7.14 (5H, m), 3.72 (1H, dd, J=3.6, 11.6 Hz), 3.50(1H, dd, J=6.8, 11.6 Hz), 3.23 (1H, m), 2.84 (1H, dd, J=6.0, 13.6 Hz),2.67 (1H, dd, J=8.4, 13.6 Hz), 2.26 (1H, m), 1.61-1.17 (14H, m), 0.89(3H, t, J=7.2 Hz), 0.86 (3H, t, J=7.2 Hz);

Melting point: 62.6-66.1° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 38 Crystal with (R)-(+)-2-amino-3-phenyl-1-propanol Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 8.29 10.66 5.110.15 8.71 5.2 13.33 6.64 12.0 15.94 5.56 31.2 16.61 5.33 24.8 17.874.96 23.1 19.83 4.47 100.0 21.48 4.13 41.0 24.51 3.63 14.7 26.22 3.4027.5 27.48 3.24 17.4 30.09 2.97 19.8 32.33 2.77 11.6 33.73 2.66 10.636.36 2.47 10.8

IR (ATR method): 3255, 3065, 3030, 2954, 2925, 2854, 2547, 2153, 1622,1574, 1541, 1496, 1456, 1395, 1375, 1338, 1309, 1279, 1207, 1175, 1113,1093, 1065, 1031, 997, 945, 913, 850, 787, 740, 697 cm⁻¹;

Solvent: acetonitrile, diethyl carbonate.

Example 4(15) Crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-(4-bromophenyl)ethylamine

NMR (CDCl₃): δ 7.45 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.0 Hz), 4.14 (1H,m), 2.30 (1H, m), 1.61-1.21 (17H, m), 0.92-0.86 (6H, m);

Melting point: 71.4-72.0° C.

Powder X-Ray Diffraction Spectral Data:

TABLE 39 Crystal with (R)-(+)-1-(4-bromophenyl)ethylamine Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 9.47 9.33 16.211.43 7.74 23.8 12.02 7.36 27.5 15.06 5.88 33.5 16.10 5.50 23.1 17.455.08 21.5 19.00 4.67 100.0 20.17 4.40 47.4 20.69 4.29 34.0 22.01 4.0451.5 23.12 3.84 82.2 24.11 3.69 68.3 25.55 3.48 46.5 27.43 3.25 62.729.75 3.00 44.1 32.38 2.76 35.8 34.67 2.59 32.7 35.94 2.50 31.5

IR (ATR method): 2954, 2925, 2855, 2703, 2195, 1621, 1571, 1515, 1491,1466, 1440, 1404, 1381, 1306, 1281, 1231, 1186, 1110, 1090, 1011, 898,850, 832, 819, 779, 742, 725, 716, 686 cm⁻¹;

Solvent: diethyl carbonate, acetonitrile.

Example 4(16) Crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylpropylamine

NMR (CDCl₃): δ 7.35-7.23 (5H, m), 3.85 (1H, t, J=6.8 Hz), 2.23 (1H, m),1.84-1.69 (2H, m), 1.60-1.20 (14H, m), 0.91-0.83 (9H, m);

Melting point: 85.5-86.9° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 40 Crystal with (R)-(+)-1-phenylpropylamine Diffraction angle (2θ)Half width Relative intensity (degree) (Å) (%) 12.49 7.08 28.2 13.986.33 17.6 14.44 6.13 42.9 15.63 5.66 15.1 16.38 5.41 15.1 18.50 4.7924.7 19.18 4.62 51.2 20.53 4.32 20.6 21.17 4.19 72.8 21.76 4.08 100.022.61 3.93 39.7 23.35 3.81 36.6 24.23 3.67 52.0 25.36 3.51 52.3 26.463.37 16.1 28.22 3.16 13.3 28.81 3.10 18.7 29.75 3.00 17.2 30.62 2.9215.6 31.41 2.85 12.3 32.45 2.76 13.2 33.49 2.67 11.5 35.16 2.55 14.735.72 2.51 15.0

IR (ATR method): 2950, 2926, 2855, 2665, 2215, 1622, 1561, 1525, 1457,1436, 1400, 1380, 1329, 1297, 1274, 1214, 1185, 1153, 1110, 1032, 998,913, 892, 849, 778, 760, 750, 741, 695, 673 cm⁻¹;

Solvent: diethyl carbonate.

Example 4(17) Crystal comprising (2R)-2-propyloctanoic acid and1,2-diphenylethylamine

NMR (CDCl₃): δ 7.35-7.14 (10H, m), 4.22 (1H, dd, J=5.2, 8.4 Hz), 3.03(1H, dd, J=5.2, 13.2 Hz), 2.91 (1H, dd, J=8.4, 13.2 Hz), 2.33 (1H, m),1.60 (2H, m), 1.47-1.23 (12H, m), 0.91 (3H, t, J=7.2 Hz), 087 (3H, t,J=6.8 Hz);

Melting point: 68.2-70.0° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 41 Crystal with 1,2-diphenylethylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 12.38 7.14 12.3 13.37 6.6225.1 14.04 6.30 18.2 16.50 5.37 56.3 17.73 5.00 100.0 18.80 4.72 77.819.83 4.47 77.3 21.17 4.19 34.2 22.80 3.90 44.5 24.07 3.69 41.2 25.143.54 40.0 27.06 3.29 29.8 28.35 3.15 20.0 29.25 3.05 18.5 30.66 2.9118.6

IR (ATR method): 3030, 2953, 2925, 2852, 2663, 2176, 1627, 1536, 1497,1467, 1455, 1431, 1396, 1338, 1310, 1275, 1232, 1110, 1074, 1024, 976,935, 910, 846, 795, 775, 758, 740, 697 cm⁻¹;

Solvent: acetonitrile.

Example 4(18) Crystal comprising (2R)-2-propyloctanoic acid andbenzhydrylamine

NMR (CDCl₃): δ 7.37-7.21 (10H, m), 5.24 (1H, s), 2.35 (1H, m), 1.60 (2H,m), 1.65-1.22 (14H, m), 0.91 (3H, t, J=7.2 Hz), 0.88 (3H, t, J=6.8 Hz);

Melting point: 70.5-71.1° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 42 Crystal with benzhydrylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 13.58 6.52 8.6 14.50 6.11 13.5 16.055.52 15.4 16.85 5.26 43.4 18.38 4.82 42.9 19.27 4.60 60.7 21.28 4.17100.0 21.63 4.10 76.2 22.70 3.91 42.5 23.46 3.79 52.0 24.59 3.62 21.225.85 3.44 35.0 26.48 3.36 40.7 26.93 3.31 27.8 28.31 3.15 19.5 30.032.97 15.9 31.38 2.85 17.5 33.55 2.67 15.8 36.60 2.45 15.3

IR (ATR method): 2995, 2925, 2853, 2614, 2194, 1617, 1573, 1519, 1497,1457, 1446, 1395, 1303, 1226, 1198, 1151, 1075, 1032, 1010, 998, 917,837, 809, 755, 735, 695, 641, 542 cm⁻¹;

Solvent: acetonitrile.

Example 4(19) Crystal comprising (2R)-2-propyloctanoic acid andcyclohexylamine

NMR (CDCl₃): δ 2.80 (1H, m), 2.16 (1H, m), 1.98 (2H, m), 1.77 (2H, m),1.63 (1H, m), 1.53 (2H, m), 1.41-1.12 (17H, m), 0.91-0.85 (6H, m);

Melting point: 99.1-101.1° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 43 Crystal with cyclohexylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 10.98 8.05 8.9 11.37 7.77 11.6 12.846.89 18.0 14.68 6.03 15.2 15.86 5.58 33.3 17.03 5.20 39.0 17.62 5.0342.1 18.82 4.71 100.0 20.09 4.42 54.8 20.90 4.25 71.7 21.83 4.07 75.922.54 3.94 35.6 25.40 3.50 25.2 25.98 3.43 26.5 27.91 3.19 19.8 29.073.07 21.4 30.03 2.97 21.5 31.64 2.83 18.8 33.24 2.69 16.0 35.89 2.5017.5

IR (ATR method): 2855, 2625, 2569, 2224, 1634, 1525, 1455, 1399, 1340,1313, 1285, 1246, 1140, 1115, 1073, 1050, 920, 891, 849, 801, 780, 748,641, 554 cm⁻¹,

Solvent: acetonitrile.

Example 4(20) Crystal comprising (2R)-2-propyloctanoic acid anddicyclohexylamine

NMR (CDCl₃): δ 2.80 (2H., m), 2.19 (1H, m), 1.97 (4H, m), 1.76 (4H, m),1.59 (4H, m), 1.43-1.13 (22H, m), 0.90 (3H, t, J=7.2 Hz), 0.87 (3H, t,J=6.8 Hz);

Melting point: 79.9-82.2° C.;

Powder X-ray diffraction spectral data:

TABLE 44 Crystal with dicyclohexylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 11.16 7.92 12.3 12.22 7.24 5.914.59 6.07 8.6 15.30 5.78 14.6 16.75 5.29 19.1 18.28 4.85 35.2 19.134.64 100.0 19.80 4.48 38.1 21.27 4.17 25.0 22.42 3.96 26.1 23.51 3.7825.9 25.20 3.53 20.3 30.38 2.94 12.4 31.17 2.87 15.4 33.03 2.71 12.9

IR (ATR method): 2926, 2853, 1622, 1524, 1488, 1455, 1401, 1352, 1306,1253, 1186, 1113, 1084, 1064, 1037, 980, 921, 887, 849, 805, 758, 640,596 cm⁻¹;

Solvent: acetonitrile.

Example 4(21) Crystal comprising (2R)-2-propyloctanoic acid andcycloheptylamine

NMR (CDCl₃): δ 6.60-5.40 (br, 3H), 3.06-2.96 (m, 1H), 2.22-2.12 (m, 1H),2.03-1.94 (m, 2H), 1.74-1.20 (m, 24H), 0.89 (t, J=7.2 Hz, 3H), 0.88 (t,J=8.8 Hz, 3H);

Melting point: 81.8-85.7° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 45 Crystal with cycloheptylamine Diffraction angle (2θ) Half widthRelative intensity (degree) (Å) (%) 7.98 11.07 26.6 12.29 7.20 20.714.68 6.03 22.2 16.19 5.47 16.3 17.39 5.10 29.1 18.34 4.83 71.6 19.074.65 86.4 20.01 4.43 100.0 20.98 4.23 28.7 22.05 4.03 22.8 24.19 3.6821.5 25.56 3.48 21.7 27.02 3.30 22.0 30.80 2.90 21.4 32.65 2.74 23.1

IR (ATR method): 2924, 1624, 1523, 1457, 1396 cm⁻¹;

Solvent: acetonitrile, absence of solvent.

Example 4(22) Crystal comprising (2R)-2-propyloctanoic acid andN-ethylcyclohexylamine

NMR (CDCl₃): δ 8.05-7.70 (br, 2H), 2.86 (q, J=7.2 Hz, 2H), 2.77-2.67 (m,1H), 2.22-2.13 (m, 1H), 2.06-1.98 (m, 2H), 1.82-1.74 (m, 2H), 1.67-1.48(m, 3H), 1.45-1.05 (m, 20H), 0.89 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.2 Hz,3H);

Melting point: 64.6-67.6° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 46 Crystal with N-ethylcyclohexylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 7.70 11.47 100.0 9.27 9.53 8.912.09 7.31 8.4 14.09 6.28 7.7 14.60 6.06 10.7 15.21 5.82 7.2 16.62 5.335.2 17.85 4.96 15.0 18.19 4.87 8.5 19.82 4.48 23.2 20.78 4.27 16.6 21.744.09 10.6 22.61 3.93 9.4 23.42 3.80 8.8 25.09 3.55 8.2

IR (ATR method): 2925, 1622, 1531, 1449, 1402 cm⁻¹;

Solvent: acetonitrile, absence of solvent.

Example 4(23) Crystal comprising (2R)-2-propyloctanoic acid and2,2,6,6-tetramethyl-4-piperidinol

NMR (CDCl₃): δ 5.00-4.60 (br, 3H), 4.15-4.02 (m, 1H), 2.29-2.21 (m, 1H),1.94 (dd, J=12.8, 4.0 Hz, 2H), 1.65-1.50 (m, 2H), 1.45-1.15 (m, 26H),0.89 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.0 Hz, 3H);

Melting point: 113.2-117.0° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 47 Crystal with 2,2,6,6-tetramethyl-4-piperidinol Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 9.11 9.70100.0 13.47 6.57 16.3 14.84 5.96 9.2 17.25 5.14 25.8 18.18 4.88 17.919.93 4.45 21.8 21.24 4.18 19.7 22.30 3.98 14.6 23.80 3.74 11.8 24.783.59 11.0 25.96 3.43 11.5 30.28 2.95 8.5

IR (ATR method): 3272, 2927, 1605, 1522 cm⁻¹;

Solvent: acetonitrile.

Example 4(24) Crystal comprising (2R)-2-propyloctanoic acid and2-(2-methoxyphenyl)ethylamine

NMR (CDCl₃): δ 7.21 (dt, J=7.6, 1.6 Hz, 1H), 7.14 (dd, J=7.4, 1.8 Hz,1H), 6.91-6.83 (m, 2H), 5.25-4.95 (br, 3H), 3.81 (s, 3H), 3.00 (t, J=7.0Hz, 2H), 2.84 (t, J=7.0 Hz, 2H), 2.30-2.20 (m, 1H), 1.65-1.50 (m, 2H),1.45-1.20 (m, 12H), 0.89 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H);

Melting point: 59.0-60.4° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 48 Crystal with 2-(2-methoxyphenyl)ethylamine Diffraction angle(2θ) Half width Relative intensity (degree) (Å) (%) 9.56 9.25 16.1 12.267.21 30.0 13.28 6.66 18.3 13.93 6.35 27.0 15.34 5.77 53.4 15.99 5.5435.3 16.50 5.37 32.5 17.31 5.12 23.5 18.57 4.77 32.3 19.15 4.63 58.620.04 4.43 100.0 20.74 4.28 90.6 21.65 4.10 69.2 23.52 3.78 44.1 24.483.63 35.2 25.76 3.46 37.7 26.35 3.38 45.4 27.52 3.24 28.1 29.20 3.0634.4 30.87 2.89 16.7 32.10 2.79 17.0 35.28 2.54 17.1

IR (ATR method): 2921, 1634, 1494, 1242 cm⁻¹;

Solvent: acetonitrile, absence of solvent.

Example 4(25) Crystal comprising (2R)-2-propyloctanoic acid and2-(3,4-dimethoxyphenyl)ethylamine

NMR (CDCl₃): δ 6.81 (d, J=8.0 Hz, 1H), 6.76-6.72 (m, 2H), 4.50-4.25 (br,3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.00 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.0Hz, 2H), 2.35-2.05 (m, 1H), 1.65-1.50 (m, 2H), 1.50-1.20 (m, 12H), 0.90(t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H);

Melting point: 54.3-56.6° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 49 Crystal with 2-(3,4-dimethoxyphenyl)ethylamine Diffractionangle (2θ) Half width Relative intensity (degree) (Å) (%) 8.56 10.3215.3 10.44 8.47 17.8 11.98 7.38 7.7 14.64 6.05 15.0 15.34 5.77 23.616.88 5.25 28.3 18.73 4.73 11.9 19.17 4.63 10.3 20.57 4.31 96.5 22.054.03 21.6 22.95 3.87 100.0 25.22 3.53 19.2 27.65 3.22 9.5 29.07 3.07 8.032.33 2.77 7.8

IR (ATR method): 2920, 1515, 1449, 1402, 1237 cm⁻¹;

Solvent: acetonitrile, absence of solvent.

Example 4(26) Crystal comprising (2R)-2-propyloctanoic acid andN-isopropylbenzylamine

NMR (CDCl₃): δ 7.40-7.25 (m, 5H), 5.50-5.00 (br, 2H), 3.88 (s, 2H),3.00-2.90 (m, 1H), 2.32-2.22 (m, 1H), 1.65-1.50 (m, 2H), 1.45-1.20 (m,12H), 1.17 (d, J=6.4 Hz, 6H), 0.90 (t, J=7.4 Hz, 3H), 0.87 (t, J=7.0 Hz,3H);

Melting point: 50.2-50.6° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 50 Crystal with N-isopropylbenzylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 7.97 11.08 100.0 11.34 7.8019.8 12.91 6.85 11.8 13.36 6.62 7.8 15.27 5.80 16.1 17.21 5.15 30.117.68 5.01 18.8 18.83 4.71 39.2 20.06 4.42 19.3 21.88 4.06 44.2 23.293.82 21.2 24.01 3.70 15.9 26.76 3.33 11.4 27.67 3.22 9.5 31.83 2.81 8.832.94 2.72 9.1

IR (ATR method): 2926, 1529, 1442, 1401 cm⁻¹;

Solvent: absence of solvent.

Example 4(27) Crystal comprising (2R)-2-propyloctanoic acid andN-butylbenzylamine

NMR (CDCl₃): δ 7.40-7.25 (m, 5H), 5.55-5.20 (br, 2H), 3.87 (s, 2H), 2.68(t, J=7.4 Hz, 2H), 2.32-2.24 (m, 1H), 1.65-1.50 (m, 4H), 1.45-1.20 (m,14H), 0.93-0.84 (m, 9H);

Melting point: 61.3-62.8° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 51 Crystal with N-butylbenzylamine Diffraction angle (2θ) Halfwidth Relative intensity (degree) (Å) (%) 11.71 7.55 10.1 13.84 6.3912.8 19.81 4.48 38.2 20.67 4.29 100.0 24.64 3.61 22.3

IR (ATR method): 2925, 1545, 1458, 1398 cm⁻¹;

Solvent: absence of solvent.

Example 5 Study on the Effect of Improving the Optical Purity of(2R)-2-Propyloctanoic Acid Using Dibenzylamine

The frequency of recrystallization required for increasing the opticalpurity from 95.0% e.e. to 99.5% or more was examined usingdibenzylamine. The optical purity of the crystal comprising(2R)-2-propyloctanoic acid and dibenzylamine was determined by liquidchromatography according to the method as described in Example 2 througha free (2R)-2-propyloctanoic acid and its phenacyl ester derivative.

<First Recrystallization>

(2R)-2-Propyloctanoic acid (5.0 g) of 95.0% e.e. in optical purity wasdissolved in acetonitrile (75 mL) and dibenzylamine (2.9 g) underheating at about 70° C. (outer temperature) and stirred for about 15minutes. The reaction mixture was allowed to stand for cooling for about1 hour, then cooled at about 5° C. for about 40 minutes, and filtered.The resulting crystals were washed with acetonitrile (10 mL) and driedin vacuo at about 35° C. to give the crystal comprising(2R)-2-propyloctanoic acid and dibenzylamine (7.1 g, 98.2% e.e.; yield93%).

<Second Recrystallization>

The crystal comprising (2R)-2-propyloctanoic acid and dibenzylamine (6.8g) produced in the first recrystallization was dissolved in acetonitrile(102 mL) under heating at about 70° C. (outer temperature) and stirredfor about 15 minutes. The reaction mixture was allowed to stand forcooling for about 1 hour, then cooled at about 8° C. for about 40minutes, and filtered. The resulting crystals were washed withacetonitrile (10 mL) and dried in vacuo at about 35° C. to give thecrystal comprising (2R)-2-propyloctanoic acid and dibenzylamine (4.8 g,99.5% e.e.; yield 71%).

<Results>

By twice repeated crystallization, the optical purity of(2R)-2-propyloctanoic acid reached 99.5% e.e. Recovery of the twicerepeated crystallization was 66%.

Comparative Example 1 Crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine

Using (R)-(+)-1-phenylethylamine in place of dibenzylamine, the sameoperation as in Example 1 was performed to give the title compoundhaving the following physicochemical properties. The resulting compoundswas crystals. In this Comparative Example, a variety of solvents wereexamined in the same manner as described above. The solvents used inobtaining the crystals are described in respective items. The opticalpurity of (2R)-2-propyloctanoic acid used as a starting material was95.0% e.e.

NMR (CDCl₃): δ 7.35-7.25 (5H, m), 4.18 (1H, q, J=6.4 Hz), 2.28 (1H, m),1.59-1.26 (14H, m), 1.44 (3H, d, J=6.4 Hz), 0.91-0.85 (6H, m);

Melting point: 74.3-74.8° C.;

Powder X-Ray Diffraction Spectral Data:

TABLE 52 Crystal with (R)-(+)-1-phenylethylamine Diffraction angle (2θ)Half width Relative intensity (degree) (Å) (%) 8.46 10.44 8.5 9.29 9.5114.0 10.94 8.08 54.2 11.36 7.78 38.1 12.70 6.96 38.8 15.00 5.90 74.815.91 5.57 22.0 16.70 5.30 32.7 17.27 5.13 29.0 18.46 4.80 22.4 19.224.62 50.6 19.92 4.45 35.7 21.32 4.16 59.3 21.94 4.05 100.0 23.08 3.8532.8 24.15 3.68 21.7 25.71 3.46 28.4 27.99 3.19 30.5 31.30 2.86 19.032.39 2.76 17.1 36.00 2.49 16.3 36.96 2.43 17.2

IR (ATR method): 2954, 2927, 2847, 2694, 2637, 2543, 2216, 1624, 1570,1525, 1496, 1456, 1438, 1397, 1381, 1315, 1293, 1275, 1227, 1185, 1155,1112, 1089, 1024, 1003, 989, 911, 849, 764, 755, 695, 539 cm⁻¹;

Solvent: acetone, acetonitrile, ethyl acetate, diethyl carbonate,n-heptane, diethyleneglycol dimethyl ether, water.

Comparative Example 2 Study on the Effect of Improving the OpticalPurity of (2R)-2-Propyloctanoic Acid Using (R)-(+)-1-Phenylethylamine

The frequency of recrystallization required for increasing the opticalpurity from 95.0% e.e. to 99.5% e.e. or more was examined using(R)-(+)-1-phenylethylamine. The optical purity of the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine was determinedby liquid chromatography according to the method as described in Example2 through a free (2R)-2-propyloctanoic acid and its phenacyl esterderivative.

<First Recrystallization>

(2R)-2-Propyloctanoic acid (5.0 g) of 95.0% e.e. in optical purity wasdissolved in acetonitrile (75 mL) and (R)-(+)-1-phenylethylamine (3.6 g)under heating at about 70° C. (outer temperature) and stirred for about15 minutes. The reaction mixture was allowed to stand for cooling forabout 1 hour, then cooled at about 5° C. for about 40 minutes, andfiltered. The resulting crystals were washed with acetonitrile (10 mL)and dried in vacuo at about 35° C. to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (7.9 g, 97.7%e.e.; yield 96%).

<Second Recrystallization>

The crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine (7.8 g) produced in the firstrecrystallization was dissolved in acetonitrile (117 mL) under heatingat about 70° C. (outer temperature) and stirred for about 20 minutes.The reaction mixture was allowed to stand for cooling for about 1 hour,then cooled at about 5° C. for about 40 minutes, and filtered. Theresulting crystals were washed with acetonitrile (10 mL) and dried invacuo at about 35° C. to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (6.9 g, 98.8%e.e.; yield 87%).

<Third Recrystallization>

Using the crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine (6.8 g) produced in the secondrecrystallization and acetonitrile (102 mL), the same operation as inthe second recrystallization was made to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (6.0 g, 98.9%e.e.; yield 88%).

<Fourth Recrystallization>

Using the crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine (5.9 g) produced in the thirdrecrystallization and acetonitrile (89 mL), the same operation as in thesecond recrystallization was made to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (5.2 g, 99.1%e.e.; yield 88%).

<Fifth Recrystallization>

Using the crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine (5.1 g) produced in the fourthrecrystallization and acetonitrile (77 mL), the same operation as in thesecond recrystallization was made to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (4.4 g, 99.3%e.e.; yield 87%).

<Sixth Recrystallization>

Using the crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine (4.3 g) produced in the fifthrecrystallization and acetonitrile (65 mL), the same operation as in thesecond recrystallization was made to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (3.7 g, 99.4%e.e.; yield 86%).

<Seventh Recrystallization>

Using the crystal comprising (2R)-2-propyloctanoic acid and(R)-(+)-1-phenylethylamine (3.6 g) produced in the sixthrecrystallization and acetonitrile (54 mL), the same operation as in thesecond recrystallization was made to give the crystal comprising(2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (3.0 g, 99.6%e.e.; yield 83%).

<Results>

(2R)-2-propyloctanoic acid having the optical purity of 99.5% e.e. ormore was obtained by 7 repeated crystallizations. Recovery of 7 repeatedcrystallizations was 40%.

Comparative Example 3 Study on Crystallization Using(2R)-2-Propyloctanoic Acid and a Variety of Amines (Study-1)

(2R)-2-Propyloctanoic acid (1 g, 5.4 mmole) produced in ReferenceExample 4 was mixed with the following respective amines (5.4 mmole),and the mixture was heated for dissolving, then allowed to stand at roomtemperature for about 24 hours, and further at about 5° C. for about 24hours. Thus, it was confirmed whether solids were precipitated or not.

<Amines Examined: 46 Species>

Cyclopropylamine [CAS: #765-30-0], 2-methoxyethylamine [CAS: #109-85-3],trimethylamine [CAS: #75-50-3], 2-dimethylaminoethanol [CAS: #108-01-0],2-amino-2-methyl-1-propanol [CAS: #124-68-5], N,N-dimethylethylamine[CAS: #598-56-1], 3-methoxypropylamine [CAS: #5332-73-0],2-ethoxyethylamine [CAS: #110-76-9], 1-methylpyrrolidine [CAS:#120-94-5], N-amylamine [CAS: #110-58-7], N-methylbutylamine [CAS:#110-68-9], N,N-dimethylisopropylamine [CAS: #996-35-0],3-dimethylamino-1-propanol [CAS: #3179-63-3], cyclopentylamine [CAS:#1003-03-8], isoamylamine [CAS: #107-85-7], 3-ethoxypropylamine [CAS:#6291-85-6], 2-diethylaminoethanol [CAS: #100-37-8],1-(2-hydroxyethyl)pyrrolidine [CAS: #2955-88-6], 4-methylpiperidine[CAS: #626-58-4], N-(2-hydroxyethyl)morpholine [CAS: #622-40-2],1-methylpiperidine [CAS: #626-67-5], hexamethyleneimine [CAS:#111-49-9], N-ethyl-N-butylamine [CAS: #13360-63-9],2-(butylamino)ethanol [CAS: #111-75-1], bis(2-methoxyethyl)amine [CAS:#111-95-5], aminomethylcyclohexane [CAS: #3218-02-8],N-methylcyclohexylamine [CAS: #100-60-7], 1-ethylpiperidine [CAS:#766-09-6], N-piperidineethanol [CAS: #3040-44-6], 2-methoxybenzylamine[CAS: #6850-57-3], 2-phenylethylamine [CAS: #3600-86-0],N-methylbenzylamine [CAS: #103-67-3], 1-butylpyrrolidine [CAS:#767-10-2], N,N-dimethylcyclohexylamine [CAS: #98-94-2], piperonylamine[CAS: #2620-50-0], 4-methoxybenzylamine [CAS: #2393-23-9],N,N-diisopropylethylamine [CAS: #7087-68-5], N-benzylethanolamine [CAS:#104-63-2], 2,2,6,6-tetramethylpiperidine [CAS: #768-66-1],1,2,3,4-tetrahydroisoquinoline [CAS: #91-21-4],2-(4-methxoyphenyl)ethylamine [CAS: #55-81-2], tripropylamine [CAS:#102-69-2], N,N-diethylcyclohexylamine [CAS: #91-65-6],2-(dibutylamino)ethanol [CAS: #102-81-8], 4-benzylpiperidine [CAS:#31252-42-3], and tributylamine [CAS: #102-82-9].

<Results>

Among the above 46 species of amines, when cyclopentylamine,aminomethylcyclohexane, 2-methoxybenzylamine, 4-methoxybenzylamine, and2-(4-methoxyphenyl)ethylamine were used, solids were precipitated, butthe remaining other amines precipitated no solid.

The resulting 5 species of solids were analyzed by a powdered X-raydiffraction analysis (under the condition as described in Example 1),indicating that the precipitates were not crystal.

Comparative Example 4 Study on Crystallization Using(2R)-2-Propyloctanoic Acid and a Variety of Amines (Study-2)

(2R)-2-Propyloctanoic acid (1 g, 5.4 mmole) produced in ReferenceExample 4 was mixed with acetonitrile (10 mL) and the following 8species of amines (5.4 mmole), and the mixture was heated fordissolving, then allowed to stand at room temperature for about 24hours, and further at about 5° C. for about 24 hours. Thus, it wasconfirmed whether solids were precipitated or not. When no dissolvingoccurred under heating, after addition of water (1 mL), the sameoperation was made, or using methanol or ethanol in place ofacetonitrile, the same operation was made.

<Amines Examined; 8 Species>

2-Amino-2-methyl-1,3-propanediol [CAS: #115-69-5], 4-hydroxypiperidine[CAS: #5382-16-1], 4-hydroxy-1-methylpiperidine [CAS: #106-52-5],1-benzyl-4-hydroxypiperidine [CAS: #4727-72-4], Tris [CAS: #77-86-1],L-arginine [CAS: #74-79-3], L-lysine [CAS: #56-87-1], and L-histidine[CAS: #71-00-1].

<Results>

No solid was precipitated in all of the above 8 amines.

Comparative Example 5 Study on Crystallization Using(2R)-2-Propyloctanoic Acid and an Alkali Metal or Alkaline Earth Metal

According to the following table, (2R)-2-propyloctanoic acid produced inReference Example 4 was mixed with an alkali metal hydroxide or analkaline earth metal hydroxide under stirring, then concentrated, andthen lyophilized; thus, it was confirmed whether solids wereprecipitated or not.

TABLE 53 (2R)-2-Propyloctanoic acid Base 1.86 g, 10 mmol aqueous 1 mol/Lsodium hydroxide (NaOH) solution (10 mL, 10 mmol) 1.86 g, 10 mmolaqueous 1 mol/L potassium hydroxide (KOH) solution (10 mL, 10 mmol)0.186 g, 1 mmol  Calcium hydroxide (Ca(OH)₂) (37 mg)/water (30 mL) 0.186g, 1 mmol  Barium hydroxide octahydrate (Ba(OH)₂•8H₂O) (157 mg)/water(10 mL) 1.86 g, 10 mmol Cesium hydroxide (CsOH) (1.49 g)/water(5 mL)

<Results>

When sodium hydroxide, potassium hydroxide, barium hydroxideoctahydrate, and cesium hydroxide were used, the resulting salts (sodiumsalt, potassium salt, barium salt, cesium salt) were oil andprecipitated no solid.

When calcium hydroxide was used, a solid (calcium salt) wasprecipitated; the precipitate was analyzed by a powdered X-raydiffraction analysis (under the condition as described in Example 1),indicating that it was not crystal but amorphous.

Formulation Example 1

The following ingredients were mixed in a conventional manner and thenmade tablets; thus, 1,000,000 tablets containing 10 mg/tablet of anactive ingredient were prepared.

Crystals comprising (2R)-2-propyloctanoic acid and dibenzylamine (10kg); carboxymethylcellulose calcium (disintegrator) (2 kg); magnesiumstearate (lubricant) (1 kg); and microcrystalline cellulose (87 kg).

Formulation Example 2

The following ingredients were mixed in a conventional manner, thenfiltered through a dust-removal filter, sterilized under heating in anautoclave, and then 5 mL each distributed into 1,000,000 ampoulescontaining 20 mg/ampoule of active ingredient.

Crystals comprising (2R)-2-propyloctanoic acid and dibenzylamine (20kg); mannitol (200 kg); and distilled water (5 kL).

INDUSTRIAL APPLICABILITY

The crystals comprising (2R)-2-propyloctanoic acid and amines obtainedin the present invention are excellent materials of which thepharmacological activity of (2R)-2-propyloctanoic acid is maintained andby which a problem in pharmaceutical formulation that the material isoil can be overcome. Thus, the crystals can be used, for example, aspharmaceuticals in orally administrable solid preparations such astablets. In addition, the crystals comprising (2R)-2-propyloctanoic acidand dibenzylamine are useful as intermediates convertible into(2R)-2-propyloctanoic acid having the optical purity over 99.5% e.e.,which so far cannot be obtained and is very useful as pharmaceutical.

1. A process for producing (2R)-2-propyloctanoic acid having an opticalpurity of 99.5% e.e. or more, which comprises: dissolving(2R)-2-propyloctanoic acid having an optical purity of 70% e.e. or moreand an optically inactive amine in a solvent to give a solution;repeating the following steps (1)-(3) 0 to 3 times: (1) preferentiallycrystallizing a crystal comprising the (2R)-2-propyloctanoic acid withthe optically inactive amine from the solution; (2) separating andcollecting the precipitated crystal; (3) dissolving the crystal in asolvent to give a solution; preferentially crystallizing a crystalcomprising the (2R)-2-propyloctanoic acid with the optically inactiveamine from the solution; and separating and collecting the precipitatedcrystal to give a free (2R)-2-propyloctanoic acid.
 2. The processaccording to claim 1, wherein the optically inactive amine isdibenzylamine.
 3. (2R)-2-propyloctanoic acid having an optical purity of99.5% e.e or more.
 4. (2R)-2-propyloctanoic acid having an opticalpurity of 99.5% e.e or more, which is obtainable by the processaccording to claim
 2. 5. A pharmaceutical composition, comprising(2R)-2-propyloctanoic acid according to claim 3, and a pharmaceuticallyacceptable carrier or diluent.
 6. The pharmaceutical compositionaccording to claim 5, which is an agent for prevention, treatment and/orsuppression of symptom progression for neurodegenerative diseases,neruropathies or diseases in need of nerve regeneration.